Combination therapy in asthma: A look into current perspective

The global prevalence of asthma has been on a rise since the 1970s, concurring with a dramatic increase in healthcare costs worldwide. This disease can take a toll on the physical and emotional health of a person, thus reducing the quality of life of the person and family. (1) The reported prevalence of asthma is estimated to be 37·9 million (35·7–40·2) cases in India (2). Asthma affects the quality of life of people not only due to physical symptoms but also psychological and social effects (3). It has been observed that age ≥40 years, female gender, a pet at home, and moderate severity of asthma were four to 13 times more likely to predict a poor quality of life for patients with bronchial asthma. (4)

To combat such circumstances, the pillars of pharmacotherapy for asthma have been built upon rapid control of symptoms, reducing the severity and frequency of recurrent episodes, preventing exacerbations, and attempting to maintain optimum lung function.

Basics of Pharmacotherapy for asthma- The Global Initiative for Asthma (GINA) gives recommendations for asthma management with the objective of improving asthma symptoms and preventing exacerbations (future risk) with the lowest effective dose. (5)

While a variety of drugs, across different classes, have been used in managing asthma for a long time now, these drugs can broadly be categorized into controller and reliever drugs. (6)

Controller drugs are used regularly (regardless of symptoms) to prevent and control symptoms, minimize airway inflammation, and/or limit the likelihood of exacerbations. Inhaled corticosteroids(ICSs), leukotriene antagonists, mast cell stabilizers, and long-acting bronchodilators fall into this category. (6)

Reliever drugs, also known as 'rescue drugs' are short-acting bronchodilators that are used to alleviate acute symptoms. Short-acting beta-agonists (SABAs) or fast-acting Long-acting beta-agonists (LABAs) in combination with Inhaled Corticosteroids (ICS) are bronchodilators that represent this group. (6)

Is monotherapy with a reliever drug enough to control asthma?

SABAs, if used alone, address the bronchoconstriction but do not address the underlying inflammation. As a result of long-standing inflammation, few published literature have indicated that airway remodeling can take place in case inflammation is not treated, which leads to fixed airflow obstruction. Additionally, monotherapy with SABA can lead to receptor downregulation, impaired bronchoprotection against constrictor stimuli, rebound bronchial hyperresponsiveness, and diminished bronchodilator response to beta-agonists during acute bronchoconstriction.

Concomitant use of an ICS can help to overcome these adverse effects and address the underlying inflammation. (6)

A rationale behind such combination therapy is that the use of SABAs without concomitant inhaled corticosteroids, over a long period, has been linked to more asthma exacerbations. (6)

To gain a deeper insight into optimized asthma management, this article focuses on the benefits of combination therapy in asthma and summarizes the pharmacotherapeutic options used as a combination therapy, while elaborating on its major supporting studies.

Analyzing the importance of combination therapy in asthma- Research has shown that over-reliance on reliever therapy during attacks is one of the major causes of poor asthma control, and underuse of maintenance controller medication once the symptoms subside (5); the focus is now on combining the two to get the maximum benefits.

Rapid-acting inhaled beta-2 agonists, also called SABAs, are the bronchodilators of choice for managing acute bronchospasms in asthma. (6)

Role of inhaled corticosteroids (ICSs) in asthma-

This group reduces inflammation in the airways. They decrease inflammatory cell activity and activation, stabilize vascular leakage, reduce mucus formation, and increase the response to a SABA during an acute attack. (6)

Experts from the Indian Chest Society and the National College of Chest Physicians, note that ICSs are the controller medication of choice for the management of stable asthma. The team further elaborates that most of the clinical benefit from ICS is obtained at low to moderate doses, and should be initiated at low to moderate doses (depending on the severity of presenting symptoms). (6)

Consistent research has now confirmed that Beclomethasone is one of the few ICSs that is efficacious in improving lung function, symptom ratings, and quality of life, as well as lowering the likelihood of exacerbations and the requirement for reliever drugs. (6)

Benefits of Combining a SABA with an ICS-

Although bronchodilators have been used for a long time in managing asthmatic attacks, growing evidence on the underlying inflammatory mechanism in asthma has shifted the focus toward anti-inflammatory therapy.

Studies have documented that the combination of corticosteroids with bronchodilators is more beneficial than bronchodilators alone. (7)

Research reveals that pretreatment with an ICS further potentiates the biochemical effects of a SABA. Corticosteroids restore bronchial responsiveness to SABA, through a variety of mechanisms; thus indicating that a combination of medications that ease acute bronchospasm while also controlling inflammation is more effective than a single therapy during an acute asthma episode. (7)

Experts recommend that patients who are already on ICS for control of asthma symptoms should not stop taking their medication during the acute attack, rather the dose of inhaled steroids should be increased for 2 to 4 weeks, depending on the symptoms. (6)

Managing asthma with combination therapy -What studies highlight:

• GINA now recommends that in asthmatics adults and adolescents, the treatment should start with ICS-containing therapy as it reduces the risk of exacerbations compared with using a short-acting β2-agonists (SABAs) reliever. ICS is now also recommended for all children 6–11 years with asthma, either regularly or, in mild asthma, whenever SABA is taken for symptom relief. (8)
• A study compared the efficacy of Beclomethasone dipropionate (BDP)-Salbutamol combination versus Salbutamol alone by Metered-dose-inhaler (MDI) among 57 pediatric patients (5-12 years) with an acute attack of bronchial asthma. The participants were randomized to receive salbutamol (100 pg/puff) alone or with BDP (50 I~g/puff) by metered dose inhaler with or without the spacer. One hour after the therapy, the baseline investigations showed that BDP-salbutamol combination with spacer exhibited a better recovery rate of clinical symptoms of asthma like wheezing, respiratory rate, and improvement in peak expiratory flow rate (PEFR) with a predicted percent of 54.18 7)
• The BEST (BEclomethasone plus Salbutamol Treatment) conducted a 6-month, double-blind, double-dummy, randomized trial to assess the efficacy of regular use versus symptom-based (" Symptom-Based Controller"). The trial included 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters.,. Patients with mild asthma were randomly assigned to receive one of four inhaled treatments: placebo twice daily plus 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler as needed; placebo twice daily plus 100 μg of albuterol as needed; 250 μg of beclomethasone twice daily and 100 μg of albuterol as needed or 250 μg of beclomethasone and 100 μg of albuterol in a single inhaler twice daily plus 100 μg of albuterol as needed. The trial concluded that as-needed ICS use was as effective as daily ICS use with an improvement with respect to PEFR, FEV1 (3.05±0.03 in liters) and FEV1 (90.58±0.82 in %) use in patients with mild asthma. (9)
• A double-blind cross-over trial assessed the efficacy of Beclomethasone diproprionate(BDP)-Salbutamol combination versus Salbutamol alone by Metered-dose-inhaler(MDI) in 18 chronic asthmatics over two consecutive 4-week periods. The study noted a significant improvement in the peak expiratory flow rate and force expiratory volume (FEV1) with a value of 2.31 which was greater than the placebo where it was 2.10, and a lower mean number of rescue inhalation for the combination group (placebo-27 versus combination-10) and, significantly less use of the rescue inhaler, and better control in case of an attack than Beclomethasone diproprionate alone. The team also highlighted that better control with the combination reduces the dose of both drugs. (10)

Key pointers-

1. Achieving well-controlled asthma greatly reduces the risk of exacerbations in asthma.

2. Guidelines now recommend that asthma in adults and adolescents treatment should start with ICS-containing therapy and should not be treated solely with short-acting β2-agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and growing evidence for benefit of inhaled corticosteroids (ICS).

3. Levosalbutamol and beclomethasone combination holds the testimony of having exhibited scientifically proven clinical benefit to asthmatic patients.

Takeaway message- With statistics revealing that around 300 million people have asthma worldwide, it is likely that by 2025 a further 100 million may be affected. Despite the advances in asthma treatment in recent decades, there are still gains to be made regarding the management of asthma. (11)

Combination therapies with inhaled steroids and short-acting beta-agonists have exhibited promising results in controlling acute attacks and maintenance therapy.

As more extensive research continues to unveil the potential of combination therapy in asthma, physicians would be empowered to effectively treat bronchial asthma effectively in clinical settings.

References

1. Maiti R, Prasad CN, Jaida J, Mukkisa S, Koyagura N,Palani A. Racemic salbutamol and levosalbutamol in mild persistent asthma: A comparative study of efficacy and safety. Indian J Pharmacol 2011;43:638-43.

2. India State-Level Disease Burden Initiative CRD Collaborators (2018). The burden of chronic respiratory diseases and their heterogeneity across the states of India: the Global Burden of Disease Study 1990-2016. The Lancet. Global health, 6(12), e1363–e1374. https://doi.org/10.1016/S2214-109X(18)30409-1

3. Ibrahim NK, Alhainiah M, Khayat M, Abulaban O, Almaghrabi S, Felmban O. Quality of Life of asthmatic children and their caregivers. Pak J Med Sci. 2019 Mar-Apr;35(2):521-526. doi: 10.12669/pjms.35.2.686. PMID: 31086544; PMCID: PMC6500827.

4. Ali R, Ahmed N, Salman M, Daudpota S, Masroor M, Nasir M. Assessment of Quality of Life in Bronchial Asthma Patients. Cureus. 2020 Oct 8;12(10):e10845. doi: 10.7759/cureus.10845. PMID: 33178501; PMCID: PMC7651774.

5. Larsson, K., Kankaanranta, H., Janson, C., Lehtimäki, L., Ställberg, B., Løkke, A., ... & Ulrik, C. S. (2020). Bringing asthma care into the twenty-first century. NPJ primary care respiratory medicine, 30(1), 1-11.

6. Agarwal, R., Dhooria, S., Aggarwal, A. N., Maturu, V. N., Sehgal, I. S., Muthu, V., ... & Varma, S. (2015). Guidelines for diagnosis and management of bronchial asthma: Joint ICS/NCCP (I) recommendations. Lung India: Official Organ of Indian Chest Society, 32(Suppl 1), S3.

7. Sharma, S., Godatwar, P., & Kulkarni, L. R. (2003). Salbutamol and/or beclomethasone diproprionate in asthma. The Indian Journal of Pediatrics, 70(2), 129-132.

8. Reddel, H. K., Bacharier, L. B., Bateman, E. D., Brightling, C. E., Brusselle, G. G., Buhl, R., ... & Boulet, L. P. (2022). Global Initiative for Asthma Strategy 2021.

9. Papi, A., Canonica, G. W., Maestrelli, P., Paggiaro, P., Olivieri, D., Pozzi, E., Crimi, N., Vignola, A. M., Morelli, P., Nicolini, G., Fabbri, L. M., & BEST Study Group (2007). Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. The New England journal of medicine, 356(20), 2040–2052. https://doi.org/10.1056/NEJMoa063861

10. Clark, R. A., & Anderson, P. B. (1978). Combined therapy with salbutamol and beclomethasone inhalers in chronic asthma. The Lancet, 312(8080), 70-72.

11. Dharmage, S. C., Perret, J. L., & Custovic, A. (2019). Epidemiology of Asthma in Children and Adults. Frontiers in pediatrics, 7, 246. https://doi.org/10.3389/fped.2019.00246