A tailored approach to COPD management
Overuse and inappropriate long-term use of inhaled corticosteroid (ICS)–containing treatments in patients with chronic obstructive pulmonary disease (COPD) are associated with increased risks of infection and side effects. At the Advances in Medicine 2020 virtual meeting organized by the Chinese University of Hong Kong, Dr Marc Miravitlles of Hospital Universitari Vall d’Hebron, Barcelona, Spain, addressed important factors to consider when choosing appropriate inhaled bronchodilation therapy for different patients. He also discussed the efficacy and safety of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) dual combination therapy, such as tiotropium/olodaterol (T/O), for both initial and long-term management of COPD and prevention of exacerbations.
Backbone of COPD management
“Bronchodilation to improve lung function is crucial in COPD management, and long-acting bronchodilators [LABDs] are the basis of treatment for stable COPD,” stated Miravitlles.
“Dyspnoea is not just a symptom but a prognostic factor in patients with COPD,” he stated. “Studies have shown that physical activity level is the strongest predictor of all-cause mortality in COPD patients. Dyspnoea reduces physical activity and exercise capacity, and patients who are less active tend to have reduced survival. This vicious cycle can be broken by bronchodilation treatment, particularly with LABDs, to increase patients’ forced expiratory volume in 1 second [FEV1], thereby reducing dyspnoea, encouraging physical activity, reducing exacerbation risk and improving quality of life,” he explained. [Chest 2002;121:1434-1440; Chest 2011;140:331-342; Respiratory Medicine 2015;109:1312-1319]
Individualized management of COPD
“The clinical presentation of COPD varies widely. As a result, both initial and maintenance pharmacological treatments should be tailored according to the patient’s clinical characteristics, such as lung function, dyspnoea grade, exacerbation history and exacerbation risk,” said Miravitlles.
“The Global Initiative for Chronic Obstructive Lung Disease [GOLD] 2020 Global Strategy for the Diagnosis, Management and Prevention of COPD recommends treatment based on the patient’s GOLD group, while the Spanish COPD Guidelines 2017 broadly stratify patients into low- or high-risk and recommend determination of clinical phenotype [ie, nonexacerbators or exacerbators, and type of exacerbator] for high-risk patients for better individualized management,” he added. (Figure 1) [https://goldcopd.org/wp-content/uploads/2019/11/GOLD-2020-REPORT-ver1.0wms.pdf; Arch Bronconeumol 2017;53:324-335]
Benefits of dual LAMA/LABA treatment
“LAMA/LABA combination therapy is recommended for patients inadequately controlled by a single LABD and for all high-risk patients, except those with asthma-COPD overlap who require a different approach to treatment,” noted Miravitlles.
“Studies have shown that dual LAMA/LABA therapy improves lung function and all other outcomes, such as frequency of exacerbations, dyspnoea and quality of life, compared with monotherapy with a LABA or LAMA alone. This is likely achieved through their complementary modes of action in reducing hyperinflation, resulting in airway stabilization, decreased mucus production, increased mucocilliary clearance, improvement of symptom severity, and possibly reduction of inflammation,” he explained. (Figure 2) [Eur Respir J 2015;45:969-979; Respiratory Research 2017;18:196; Am J Resp Crit Care Med 2017;196:139-149]
A systematic review and meta-analysis of 10 randomized controlled trials, which included 10,918 patients with COPD, found that treatment with T/O provided significant improvements in lung function vs monocomponents and LABA/ICS. T/O significantly improved trough FEV1 from baseline to week 12 vs tiotropium, olodaterol and LABA/ICS by 60 mL, 90 mL and 40–50 mL, respectively, with more T/O-treated patients achieving significant improvements in dyspnoea and health status. Patients treated with T/O also showed a significant reduction in rescue medication use compared with those treated with monocomponents, with no significant differences in frequency of general and serious adverse events between T/O and monocomponents. [Respiratory Research 2017;18:196]
Targeted approach to treatment of exacerbations
“Some COPD patients have frequent and/or severe exacerbations despite maximal bronchodilation. Although these patients account for only about one-third of the global COPD population, they are at increased risk of death and are difficult to treat. ICS or ICS-containing treatments are indicated in such patients,” said Miravitlles. [N Engl J Med 2010;363:1128-1138]
“However, not all COPD patients respond to ICS, and inappropriate long-term use of ICS in COPD may be associated with increased risks of side effects such as pneumonia, tuberculosis, bone fracture and diabetes,” he noted. [Int J Chron Obstruct Pulmon Dis 2015;10:2207–2217; NPJ Prim Care Respir Med 2017;27:43; Prim Care Respir J 2013;22:92–100; Chest 2018;153:321–328; N Engl J Med 2018;378:1671-1680]
“COPD exacerbations are heterogenous and complex with respect to aetiology, inflammation and biologic exacerbation phenotypes,” Miravitlles continued. “Many studies, including IMPACT [Informing the Pathway of COPD Treatment], have also shown that blood eosinophils are a useful biomarker and that blood eosinophilic count [BEC] reflects, to some degree, the extent of eosinophilic airway inflammation and is therefore predictive of the patient’s response to ICS.” [Am J Respir Crit Care Med 2011;184:662-671; Eur Respir J 2017;49:1601464; Lancet Respir Med 2019;7:745-756; Eur Respir J 2020;55:2000881]
The GOLD and European Respiratory Society (ERS) guidelines recommend ICS-containing treatments for a selected group of patients with BEC ≥300 cells/µL and a recent history of frequent exacerbations, but not for patients with BEC <100 cells/μL. In the ERS guidelines, the BEC cut-off of 100–300 cells/μL for ICS use may vary according to the presence of other factors that modulate response, such as smoking status, frequency and severity of exacerbations, and exacerbations requiring treatment with antibiotics or oral corticosteroids. GOLD has a separate algorithm for follow-up treatment and recommends adding an ICS to LABD in patients with BEC ≥100 cells/μL who had ≥2 moderate exacerbations or one severe exacerbation, while avoiding ICS in patients with BEC <100 cells/μL. This is based on the analysis of recent trials, which demonstrated no benefit of ICS/LABA/LAMA vs LABA/LAMA therapy in patients with BEC <100 cells/μL and evidence of benefit for those with BEC >100 cells/μL. [Eur Respir J 2020;55:2000351; Eur Respir J 2020;55:2000881; N Engl J Med 2018;378:1671–1680]
The ERS guideline also recommends ICS withdrawal for patients who do not require ICS as there is sufficient evidence that ICS withdrawal has no significant impact on exacerbation frequency in these patients. (Figure 3) [Eur Respir J 2020;55:2000351; N Engl J Med 2014;371:1285-1294; Am J Respir Crit Care Med 2018;198:329-339]
Recent real-world evidence from a database analysis of 42,953 COPD patients assessed over 1 year further found that treatment with LAMA/LABA, in this case T/O, resulted in a lower risk of escalation to triple therapy, COPD exacerbations, pneumonia or an adverse outcome vs LABA/ICS, irrespective of BEC or exacerbation history. (Figure 4) [Am J Crit Care Med 2020;201:A5072]