Cardiovascular Disease and Chronic Obstructive Pulmonary Disease: Adding a Third Dimension to the ABE Global Initiative for Chronic Obstructive Lung Disease 2023 Chronic Obstructive Pulmonary Disease Classification

To the Editor:

The diagnosis of chronic obstructive pulmonary disease (COPD) is confirmed by spirometry (presence of FEV₁/FVC < 0.70), and the assessment of airflow limitation severity is based on the post-bronchodilator value of FEV₁ (% predicted) (1). However, the severity of airflow obstruction is weakly correlated to the symptoms experienced by a patient with COPD (2). The modified Medical Research Council dyspnea scale and the COPD Assessment Test are currently used to assess the severity of symptoms (3). Thus, since 2011, Global Initiative for Chronic Obstructive Lung Disease (GOLD) has proposed the combined initial COPD assessment based on the frequency and severity of exacerbations in the previous year, the level of symptoms (modified Medical Research Council dyspnea scale/COPD Assessment Test), and the severity of airflow limitation (GOLD grades 1–4). The original ABCD combined assessment tool has been modified in the 2023 GOLD document by merging groups C and D into the new group “E,” which includes all the exacerbating patients, irrespective of their symptomatic status (3). In this new classification, the basis of the initial COPD management is dual bronchodilation with long-acting β-agonists (LABA)  + long-acting muscarinic antagonists (LAMA), whereas the use of a LABA/inhaled corticosteroids (ICS) combinations is not encouraged, as the combination LABA/LAMA/(ICS) (triple therapy) has been shown to be superior to LABA/ICS in patients with an indication for the addition of an ICS. According to the GOLD 2023 document, triple therapy is an offered therapeutic choice as initial pharmacological treatment only for patients stratified at group E with ⩾300 blood eosinophils/μl (3).

Potential Benefits from Earlier Use of Triple Therapy in Patients with Cardiovascular Disease

COPD is a disease of accelerated aging and systemic inflammation, often accompanied by comorbidities, which contribute to morbidity and mortality and often complicate the therapeutic choices (4). Among common comorbidities in patients with COPD, cardiovascular diseases (CVDs) have the highest prevalence (between 13% and 68%), as both diseases share common pathological mechanisms and risk factors (5, 6). Moreover, many patients with coexisting COPD and CVD do not currently receive appropriate treatment for both conditions, this being an underrecognized unmet need in patients with such comorbidities. The latest GOLD recommendations still propose an algorithm of stepping up and down therapy by considering the patients’ characteristics and their response to treatment but not the coexistence of certain comorbidities, especially CVD (3).

There is a growing body of evidence on the benefits of the earlier use of ICS (and therefore triple therapy) in patients with COPD, especially in the subgroup of patients with COPD with increased cardiovascular risk or CVD. The Study to Understand Mortality and Morbidity in COPD (SUMMIT) trial showed that ICS, alone or in combination with a LABA, reduced FEV₁ decline in patients with moderate COPD and heightened cardiovascular risk (7). This potentially protective role of ICS on lung function decline has also been reported in a systematic review of studies comparing ICS versus non-ICS treatments (8). Furthermore, results from the Withdrawal of Inhaled Steroids During Optimized Bronchodilator Management (WISDOM) and the Study to Understand the Safety and Efficacy of ICS Withdrawal from Triple Therapy in COPD (SUNSET) trials have shown that patients with severe COPD on triple therapy experienced a greater decrease in lung function when ICS was discontinued (9, 10).

Recent Evidence on the Beneficial Effects of the Combination of Medium-Dose ICS with Dual Bronchodilation in Patients with COPD with CVD or Risk

The large InforMing the PAthway of COPD Treatment (IMPACT) and Efficacy and Safety of Triple Therapy in Obstructive Lung Disease (ETHOS) trials have shown that triple-therapy fixed-dose combinations involving a medium dose of ICS resulted in lower rates of moderate or severe COPD exacerbations when compared with LABA/ICS or LABA/LAMA in symptomatic patients with a history of exacerbations (11, 12). These two trials also provided, in further analyses, interesting evidence on mortality reduction with triple therapy compared with maximal (dual) bronchodilation (13, 14). In the paper by Martinez and colleagues, a signal for the reduction of cardiovascular events with triple therapy versus the LABA/LAMA combination was shown (14). The absence of a mortality signal in earlier trials (7, 15) may be related to the fact that ICS was not used on top of effective dual bronchodilation (16). The beneficial effect of LABA/LAMA combination therapy on cardiac function in patients with COPD and lung hyperinflation has been previously reported in the Study to Assess the Effect of QVA149 (Indacaterol Maleate/Glycopyrronium Bromide) on Cardiac Function in Patients with COPD (CLAIM) study (17), suggesting that effective bronchodilation should be the basis of the management of such patients.

Potential Consideration of Cardiovascular Comorbidities in the Choice of Treatment and the Proposal of a Modified ABE+ Figure

Based on the aforementioned body of evidence, we may hypothesize that the use of triple therapy (effective dual bronchodilation plus ICS) as an initial treatment could be considered in appropriately selected symptomatic and/or exacerbating patients with COPD with a history of or at increased risk for CVD. Thus, we propose adding a third dimension to the ABE classification, by characterizing patients as B+ or E+ if they are more symptomatic and/or exacerbating, respectively (Figure 1). This schematic proposal provides the implication for the earlier treatment of appropriate patients with COPD and cardiovascular comorbidities and/or risk with triple therapy, based on the treating clinicians’ judgment; however, this needs to be supported by appropriately designed future trials.

Figure 1.

The proposed ABE+ assessment tool. +Patients with CVD or increased cardiovascular risk. CAT = chronic obstructive pulmonary disease assessment test; CVD = cardiovascular disease; mMRC = modified Medical Research Council dyspnea scale.