In an interview with Omnihealth Practice, Dr. Lam, Chung-Mei Jamie presented the updates of the 2023 Global Initiative for Chronic Obstructive Lung Disease (GOLD) report of chronic obstructive pulmonary disease (COPD). She also elaborated on the data of the efficacy and safety of dual therapy of long-acting beta-2 agonist (LABA) and long-acting muscarinic antagonist (LAMA), the use of inhaled corticosteroid (ICS), and shared a case scenario that pinpointed the problem of overprescribing ICS in patients.

The global and local burden of COPD

COPD is a chronic airway disease characterized by a persistent airflow obstruction due to chronic bronchitis or emphysema.¹ According to the World Health Organization (WHO), COPD is the third leading cause of death worldwide with about 3.23 million deaths in 2019, of which >90% occurred in patients in the low- and middle-income countries.² In a Hong Kong study of COPD patients requiring hospital admission, patients were mostly elderly with a mean age of 78 years having ≥1 comorbidities.³

Updates in the 2023 GOLD report for COPD management

A new definition of COPD was proposed in the 2023 GOLD report.⁴ COPD is revised as a heterogeneous lung condition characterized by chronic respiratory symptoms, e.g., dyspnea, cough, and sputum production, due to abnormalities of the airways and/or alveoli that cause persistent and often progressive airflow obstruction.⁴ Objectively, COPD is classified based on the lung function of forced expiratory volume in the first second (FEV₁) and predicted into 4 classes with GOLD 1 having the highest FEV₁ predicted (≥80%) and GOLD 4 having the lowest FEV₁ predicted (<30%).⁴ Patients could also be classified into 3 categories based on the exacerbation history and symptoms.⁴ Group A and B patients have a low risk with 0-1 moderate exacerbations that can be managed at home and not leading to hospital admissions, but Group B patients suffer from daily symptoms more often.⁴ Group E, which was previously known as Group C and D, refer to patients with high risk of exacerbations.⁴

Over the years, many drugs have been developed for COPD management with a shift in the trend from short-acting to long-acting bronchodilators, such as LABA and LAMA. “The typical management strategy in the past was a fixed combination of LABA and ICS, but we are shifting to the use of a combination of LABA and LAMA nowadays,” Dr. Lam highlighted.

The GOLD report recommends LABA and LAMA in all COPD patients as a central part to the symptoms management.⁴ Dual bronchodilators of LABA and LAMA are especially recommended for patients with dyspnea.⁴ For patients with frequent exacerbations, the combination of dual bronchodilators or triple therapy of LABA + LAMA + ICS is recommended.⁴ Other anti-inflammatory drugs may also be considered, such as roflumilast for patients with chronic bronchitis and FEV₁ <50%, and azithromycin for previous smokers with a lot of sputum and recurrent infection.⁴

Consideration of individualized treatment for COPD patients

Dr. Lam emphasized that COPD individualized treatments are based on reviewing patient’s symptoms, mainly dyspnea and exacerbations, an assessment of patient’s inhaler technique and compliance, as well as non-pharmacological approaches before escalating or de-escalating treatment.⁴

Diagnosis establishment starts with an initial assessment to examine patient’s risk factors, lung function (i.e., FEV₁), symptoms and exacerbation history.⁴ Patients with a history of hospitalizations for acute exacerbations, moderate exacerbations ≥2 times per year, blood eosinophil counts ≥300 cells/μL, and a history of overlapping asthma can add ICS to LABA and LAMA.⁴ ICS may also be considered in patients with 1 moderate exacerbation per year with blood eosinophil counts between 100 to 300 cells/μL.⁴ The report did not support the use of ICS in patients with a history of repeated pneumonia, blood eosinophil counts <100 cells/μL, or a history of mycobacterial infection.⁴

A set of real-world data from the United Kingdom (UK) highlighted that ICS treatments have been inappropriately prescribed and overused in COPD patients who do not meet the COPD guideline for ICS use.⁵ ICS is currently overused in >70% of patients receiving an ICS-containing therapy, but only <20% of patients should need it based on the GOLD report.⁶

According to Dr. Lam’s suggestions, ICS withdrawal should be considered in patients who do not have any exacerbations in the past 3 months with blood eosinophil counts ≤300 cells/μL.⁷ If the blood eosinophil counts >300 cells/μL without any risk of pneumonia or bacterial exacerbation, ICS could be continued.⁷  Otherwise, the ICS dose should be reduced or changed to an ICS with a lower risk of side effects or potency.⁷ The proportion of patients receiving triple therapy within 1 year of diagnosis seems to be consistent in all GOLD classes.⁵

The choice of inhaler device should be individually tailored depending on the access, cost, prescriber, and most importantly, the patients’ preferences.⁴ The study comparing different inhaled devices showed different degrees of throat deposition and inspiratory effort needed.⁸ Soft mist inhaler seems to have the lowest degree of throat deposition and the highest degree of deposition in the lungs even at a relatively lower flow rates in comparison with other inhalers.⁸ Hence, Dr. Lam stressed that we should know the severity of COPD and how much effort patients would be able to put in so that the drug can reach the lungs.

Evidence of LABA + LAMA as a typical regimen for COPD

In the TONADO 1 and 2 phase III studies, the combination of LAMA (tiotropium) and LABA (olodaterol) once daily for 24 weeks showed a significantly better lung function and improved health-related quality of life than LABA or LAMA monotherapy in patients with moderate to very severe COPD (figure 1).⁹

The ENERGITO study comparing once-daily tiotropium + olodaterol with twice-daily salmeterol + fluticasone propionate demonstrated a significant improvement in FEV₁ values over 24 hours after 6 weeks of treatment (figure 2).¹⁰

A real-world observational study showed a significant exacerbation reduction among patients with blood eosinophil counts >6% (44%; HR=0.66; 95% CI: 0.46-0.94) or those with a history of ≥2 exacerbations (17%; HR=0.83; 95% CI: 0.70-0.98) in the prior year when using triple therapy compared with dual therapy.¹¹ Hence, apart from patients with high blood eosinophil counts or a history of ≥2 exacerbations, LAMA + LABA seemed to be sufficient to control the symptoms as there was an increased risk of pneumonia with triple therapy.

In the IMPACT study, the rate of moderate or severe COPD exacerbations with the use of triple therapy was 0.91 per year, when compared with that of fluticasone furoate + vilanterol [1.07 per year; rate ratio (RR) =0.85; 95% CI: 0.8-0.9; p=0.001] and umeclidinium + vilanterol (1.21 per year; RR=0.75; 95% CI: 0.7-0.81; p=0.001) when compared with placebo, which demonstrated that triple therapy seemed to reduce moderate or severe COPD exacerbation.¹²

The real-world data also demonstrated that the initiation with LABA + ICS or LAMA monotherapy had a comparable incidence of moderate or severe COPD exacerbations during the first year of use (HR=0.95; 95% CI: 0.90-1.01).¹³ LABA-ICS was only superior to LAMA in reducing the incidence of exacerbation when blood eosinophil concentrations were greater than 4% of the white blood counts (WBCs).¹³

Moreover, ICS has been shown to have safety concerns. The incidence of severe pneumonia was 46% higher in triple therapy than in dual therapy (HR=1.46; 95% CI: 1.03-2.06), which was consistent with the 60% increase in pneumonia in the IMPACT trial.¹¹ A meta-analysis of 12 different randomized controlled trials with approximately 11,000 total subjects showed a reduction in the risk of pneumonia if not having ICS for COPD patients (OR=1.55; 95% CI: 1.20-2.01).¹⁴

The IMPACT study demonstrated a significantly increased incidence of pneumonia with LABA + LAMA + ICS (8%) compared with LABA + LAMA (5%), with a higher risk of pneumonia associated with the use of triple therapy (HR=1.53; 95% CI: 1.22-1.92; p<0.001).¹² Similarly, the ETHOS study concluded that the incidence of pneumonia ranged from 3.5% to 4.2% in the triple therapy group, with a higher incidence in patients receiving a higher dose of ICS compared with only 2.3% in the LABA + LAMA group.¹⁵

In the WISDOM trial, COPD patients were started on triple therapy, and then randomized to either continued triple therapy or stepped down to dual bronchodilators.¹⁵ The probability of exacerbation was non-inferior between the 2 groups (HR=1.06; 95% CI: 0.94-1.19; p=0.35).¹⁶ Therefore, in other words, discontinuing ICS did not increase the rates of exacerbations.¹⁶

Recommendations on the use of ICS-containing therapies by other Respiratory Societies

The 2020 American Thoracic Society (ATS) guidelines recommended ICS withdrawal in patients without any exacerbations.¹⁷ Based on their assessment of pooled data from 2 different clinical trials with over 3,500 patients, patients who were de-escalated from triple therapy to LAMA + LABA had a lower risk of pneumonia but it was not statistically different from patients on triple therapy.¹⁷

The 2020 European Respiratory Society (ERS) guidelines also included a recommendation for ICS withdrawal, particularly in patients with eosinophil counts <300 cells/μL and without frequent exacerbations.¹⁸ However, ICS should not be withdrawn in patients with blood eosinophil counts ≥300 cells/μL, with or without a history of frequent exacerbation. If ICS was considered to be withdrawn, patients should be treated with 1 or 2 long-acting bronchodilators.¹⁸

Individualized management plan in a case scenario

To show the importance of individualized management plan and the need of ICS withdrawal, Dr. Lam shared a clinical case of a 70-year-old male patient. He lived alone and was a chronic heavy smoker. He had a past medical history of hypertension, COPD and gout. His medications included diuretics, inhalers, gouty therapy, and antihypertensive drugs. Chest X-ray showed hyperinflated chest. He presented to Dr. Lam’s clinic with palpitations, shortness of breath, ankle oedema and a productive cough for 2 weeks. His laboratory findings were elevated WBC, normal eosinophil level, and a decompensated type II respiratory failure on arterial blood gas (ABG) with an FEV₁ predicted of 36% on spirometry. Electrocardiograph showed atrial fibrillation (AF).

This patient suffered from an acute infective exacerbation of COPD, acute on chronic decompensated type II respiratory failure, AF and congestive heart failure (CHF), and was admitted in hospital for further management. Dr. Lam switched his inhaled therapy from LABA + ICS to LABA + LAMA. He seemed to have poor social support and infective COPD exacerbations. The entire management plan included optimizing his blood pressure and AF control, as well as referring him to see a geriatrician for assessment due to his comorbidities and polypharmacy. He needed to be regularly followed up and to have community nurse support. This patient was also taught to monitor his own symptoms, use inhaler properly (puff technique) and understand the importance of drug compliance as part of patient education. As he was living alone, Personal Emergency Link Service was adopted so that he could ask for help instantly when needed. Finally, this management plan worked out well for this particular patient after withdrawing his ICS treatment, with less infective exacerbation and hospitalizations.

Conclusion

Dr. Lam reminded the importance of individualized treatment for COPD patients. The combination of LABA + LAMA should be recommended for all COPD patients as maintenance COPD inhaled therapies, given the improved efficacy, safety and particularly lower pneumonia incidence when compared with bronchodilator monotherapy and triple therapy of bronchodilators and ICS.^9-15 Patients with high blood eosinophil counts and frequent exacerbations are better candidates for ICS.¹³