ICS in COPD: Is three better than two?

Chronic obstructive pulmonary disease (COPD) affects more than 251 million people across the globe. Inhaled corticosteroid (ICS) remains one of the most commonly prescribed inhaled medication in the management of COPD despite the Global Initiative for Obstructive Lung Disease (GOLD) committee limiting the recommended use of ICS for certain individuals. In a webinar series sponsored by Boehringer Ingelheim on the 10^th, 17^th, 24^th of October 2020, Dr Patrick Gerard Moral, Associate Professor of Department of Medicine at UST Faculty of Medicine and Surgery; Dr Daniel Tan, Chairman of Health Justice Foundation and a Professor of Medicine, University of the East College of Medicine; and Dr Dave Singh, Professor of Clinical Pharmacology and Respiratory Medicine, University of Manchester, United Kingdom, emphasized the importance of physical activity in COPD and discussed the use of ICS among patients with COPD.



Dr Patrick Gerard Moral




Dr Daniel Tan




Dr David Singh



How does physical activity impact the quality of life among patients with COPD?  

Dyspnea is often the presenting complaint of patients with COPD. “As a consequence, this limits the physical activity and eventually, patients will abandon any forms of physical exercise,” Dr Moral said. “When you decrease your physical activity, your quality of life also progressively decreases”. He added that the “Reduction in physical activity is bidirectional. When you reduce your physical activity, it can reduce your quality of life, make you anxious and depress, and impact your disease prognosis. But at the same time, the reduction in quality of life, may cause a reduction in physical activity further.” Moreover, this decrease in physical activity causes worsening exacerbation and further progression of the disease. [Reardon JZ, et al. Am J Med. 2006;119:S32–S37.]

 However, the decrease in physical activity started due to the symptoms which limit their exercise tolerance. Thus, as Dr Moral mentioned, “The management of symptoms, particularly dyspnea, is essential in maintaining or increasing the level of physical activity.


Is Three Always Better Than Two?

To reduce symptoms, decrease the frequency and severity of exacerbations, and improve the exercise tolerance of patients with COPD, pharmacological therapy should be initiated. Each treatment regimen is individualized and may differ between patients. [Global Initiative for Chronic Obstructive Lung Disease. 2020.]

However, as Dr Moral stated, “LAMA [long acting muscarinic antagonis]  / LABA [long acting beta agonist]  is what we consider as one of our primary treatment especially for those with breathlessness”. However, “In your patients who are complaining of intolerance despite dual therapy, they say that that is the only time you may want to try triple therapy using an ICS over dual therapy,” Dr Moral added.

“How can ICS dilate the airways if the main problem is emphysema,” Dr Tan asked.

A multicenter, multinational, randomized, double-blind, double-dummy, active-controlled, four-treatment, complete crossover study was conducted by Beeh KM, et al. The trial compared the effect of the LABA/LAMA and LABA/ICS among 288 patients with stable COPD who complained of dyspnea and/or exercise intolerance. Results showed that LABA/LAMA improved the lung function greater than that of LABA/ICS (p<0.001). Moreover, there is also a greater reduction in air trapping and therefore, lung hyperinflation with LABA/LAMA compared to LABA/ICS. Dr Tan, using the study, emphasized, “Using FVC [forced vital capacity] as a surrogate marker in the ability to deflate the lung, which one is better? It is not the ICS combined regimen. The LABA/LAMA is more effective. So when it is about the symptoms, the initial choice is the long acting bronchodilator or the LABA/LAMA without the ICS. It is not there because it is not meant to do the improvement you want to see.” This study also suggest that the LABA/ICS may not be the most effective treatment for improving lung function in individuals with moderate to severe COPD. [Beeh KM, et al. Int J Chron Obstruct Pulmon Dis. 2016;11:193–205.]

For patients experiencing COPD exacerbations, Dr Tan advised on asking the patients, “Are you having a continuous experience of recurrent exacerbations despite the fact that you are on maintenance of the most potent bronchodilator?”

“We just don’t start them [patients experiencing COPD exacerbation] on triple therapy. We have to consider, is the patient presenting with high blood eosinophil count? If the answer is yes, you could add ICS. If the patient has chronic bronchitis, which means chronic productive phlegm of more than 3 months in a year for two successive years, consider roflumilast and just be careful about the GI [gastrointestinal] side effects. But the guidelines in the use of roflumilast says we don’t give that unless the patient is already on an ICS maintenance. If the patient is presenting with frequent infection, so instead of a short course, I will maintain them on long term azithromycin, which is evidence-based but watching out for bacterial resistance and hearing loss.”

The question now would be, for patients with COPD, who complains of dyspnea and/or exercise intolerance, is triple therapy more effective compared to dual or monotherapy? “The answer is this,” Dr Tan started. “If it were given for acute exacerbation frequency, we will be assured that it will go down by 25% compared to dual therapy. But beware. There will be a 47% [increased] risk of pneumonia compared with the LABA/LAMA.”

“The intent of the triple therapy is not for the dyspnea because there is no change in the dyspnea by adding an ICS,” Dr Tan emphasized. Hence, “Triple therapy is not superior to maintenance long-acting dual bronchodilator therapy, except if the patient has a history of more than one exacerbations in the past year requiring antibiotics and/or steroid or hospitalization in whom the benefit of the exacerbation reduction will outweigh the increased risk of pneumonia.”

Therefore, three is not always better than two.   Given this, “Which patients should best receive this medicine [ICS],” Dr Singh asked.


Latest update: What is the use of ICS for patients with COPD?

“Patients with higher blood eosinophilic count have a bigger response to corticosteroids because they have higher eosinophils in their lungs,” Dr Singh stated. In addition, patients who will benefit from ICS with their dual therapy include “those who consistently show in acute bronchodilator therapy, an acute reversible improvement > 12% from the baseline, or those who are suffering from chronic bronchiolitis as underlying disease,” Dr Tan said. The GOLD study presented a table showing the factors that needs to be considered when initiating ICS therapy in combination with one or two long acting bronchodilators.

Table. Factors to consider when initiating inhaled corticosteroid

 

^{COPD, chronic obstructive pulmonary diseaseAdapted from Global Initiative for Chronic Obstructive Lung Disease.
Available at: https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf Accessed 16 November 2020.}

“What is the problem with inhaled steroids,” Dr Singh asked. Use of ICS can increase the risk of osteoporosis. “Half of your COPD patients are female with lots of risk factors for osteoporosis, so we have to be careful about the use of our corticosteroids,” Dr Singh emphasized. “We also talk a lot about pneumonia [as one of the complications in the use of ICS]. The common features of all these triple therapy studies are that the ICS-containing arms had more pneumonia incidents,” Dr Singh stated.   Overall, the management of COPD starts with managing its symptoms to increase physical activity and thus, improve the quality of life for these patients. There should be a holistic approach in its management with pharmacological therapy used for symptom control, improvement in the quality of life and decreasing exacerbation rates. Long acting bronchodilators are the main pharmacological therapy in the management of COPD and ICS can be added if certain factors have been met. Management of COPD for each patient should be individualized and all the factors and considerations should be assessed prior to therapy initiation and maintenance. As Dr Tan concluded, “We are not just there to treat the disease, we are a healer of a disease.”