Should all patients with COPD be treated with inhaled triple therapy?

Extract

COPD is an under-recognised global epidemic, affecting 480 million people worldwide, which is approximately 10% of the adult population [1]. COPD is at present the third leading cause of mortality [2]. Over the next 30 years, the number of patients with COPD is expected to increase by 23%, such that by 2050 there will be nearly 600 million patients living with COPD [1]. The economic burden of COPD is staggering. In the United States alone, the annual healthcare expenditures related to the care of COPD patients approaches USD 40 billion per year [3]. Because of the soaring rates of COPD across the world, the best estimates suggest that COPD will cost the world's economy USD 7.8 trillion in direct and indirect expenditures over the next 30 years [4].

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Triple therapy should be initiated earlier in the course of COPD https://bit.ly/3Nh9W6j

COPD is an under-recognised global epidemic, affecting 480 million people worldwide, which is approximately 10% of the adult population [1]. COPD is at present the third leading cause of mortality [2]. Over the next 30 years, the number of patients with COPD is expected to increase by 23%, such that by 2050 there will be nearly 600 million patients living with COPD [1]. The economic burden of COPD is staggering. In the United States alone, the annual healthcare expenditures related to the care of COPD patients approaches USD 40 billion per year [3]. Because of the soaring rates of COPD across the world, the best estimates suggest that COPD will cost the world's economy USD 7.8 trillion in direct and indirect expenditures over the next 30 years [4].

What can be done to curb the growing burden of COPD? The most effective method is prevention, by reducing cigarette smoking rates and work-related exposures and improving air quality [5, 6]. Another is to implement relatively “safe” disease-modifying therapies that can beneficially modify the course of a disease for patients with early stages of the disease. This approach has been proven to be particularly effective in reducing morbidity and mortality related to ischaemic heart disease by the widespread adoption of statin therapy for secondary prevention of patients with elevated serum cholesterol levels [7]. Much like statins, inhaled therapies are generally inexpensive and safe. However, are they effective in modifying disease?

One of the earliest clues that they are was evinced in the UPLIFT trial [8]. In this 4-year study, the UPLIFT investigators showed that once-daily use of tiotropium, a long-acting muscarinic antagonist (LAMA), increased forced expiratory volume in 1 s (FEV₁) by 50 to 100 mL, reduced exacerbations, and improved symptoms of patients living with moderate to severe COPD [8]. In patients with mild COPD, the results were even more striking with FEV₁ improving by 130 to 160 mL, and the annual rate of FEV₁ change improving by 20 to 30 mL·year⁻¹. Importantly, the risk of exacerbation was reduced by 40% in this group of patients through the use of tiotropium [9]. The use of dual long-acting bronchodilators such as long-acting β2-agonist (LABA)/LAMA combinations has produced better results. In patients with moderate-to-severe COPD, they have been shown to improve FEV₁ by approximately 50 mL and reduce the risk of exacerbations compared with LABA or LAMA alone [10]. Importantly, the safety profiles of LABA/LAMA combinations or LAMA alone have been shown to be acceptable in patients with COPD. Together, these data suggest that LABA/LAMA combinations or LAMA alone can be used to modify the natural course of COPD patients.

Even more promising are inhaled corticosteroid-LABA-LAMA combinations (“triple” therapy) for disease modification in COPD. In patients with severe COPD, the use of triple therapy results in an approximate 50 mL improvement in FEV₁ and a significant reduction in exacerbations over 1 year compared with LABA/LAMA combination therapy [11]. Intriguingly, in one large phase III therapeutic trial, the use of triple therapy was associated with improved survival and a lower risk of major adverse cardiovascular events over 1 year [12], possibly by reducing exacerbations, which are known triggers of acute cardiovascular events [13], attenuating airway and systemic inflammation and improving patient symptoms [14, 15]. The only important safety signal related to triple therapy was the increase in the relative risk of pneumonia as an adverse event [12], though given the low baseline risk, the absolute risk increase was small [12]. Moreover, both LABA/LAMA and triple therapy are relatively inexpensive compared with small molecular therapies or biologics, which are used in other chronic lung diseases such as cystic fibrosis or asthma. Because of this, despite their soaring popularity in high-income countries, the worldwide sales of inhaled triple therapy are less than USD 4 billion per year; similar figures are found for the sales of LABA/LAMAs and LAMA alone [16]. These costs are relatively small in comparison to those of biologics, which are used far less frequently. For example, the 2023 worldwide sales of dupilumab exceeded USD 13 billion [17]. Thus, LABA/LAMA and triple therapy fulfil two of the three important criteria as long-term disease modifiers: 1) relatively low unit cost, and, 2) an acceptable safety profile. However, the third criterion remains elusive. For therapeutics to qualify as disease-modifiers, they must be shown to produce long-term benefits in the target patient population. Although the efficacy data have been promising for both LABA/LAMAs and triple therapy, they have been generated in short-term (mostly one-year) studies. As disease-modifiers typically have to be initiated early in the course of the disease for maximal impact, long-term data are needed to fully evaluate the role of these therapeutics as potential disease modifiers in COPD.

In the current issue of ERJ Open Research, Singh et al. [18] provide state-of-the-art modelling data to project the benefit of triple therapy over time. They used published data to quantify disease progression of COPD patients from 40 to 75 years of age. They then modelled the scenario of using LABA/LAMA combination therapy beginning at age 45 years, which escalated to triple inhaled therapy by age 50 years. They found that compared to no treatment, the use of the LABA/LAMA combination preserved 159 mL of FEV₁ (approximately 10% of the baseline FEV₁). Further, the use of inhaled triple therapy increased FEV₁ by 217 mL compared with LABA/LAMAs and 377 mL compared with no treatment. If these data can be validated, the improvement in FEV₁ over time with triple therapy would be clinically significant, delaying progression of COPD by ∼25%. Singh et al. [18] also showed that the institution of LABA/LAMA combination or triple therapy led to significant improvements in symptoms and health status of patients. Most strikingly, their models showed that the long-term use of LABA/LAMA or triple therapy reduced total mortality by 5.4% and 12.0%, respectively, by 75 years of age. These estimated benefits of LABA/LAMA and triple therapies may be conservative as they do not account for potential reductions in cardiovascular events and lung cancer, which have been associated with the use of triple therapy containing inhaled corticosteroids [11, 12, 19].

However, these findings should be interpreted within the limitations of this modelling study. First, the elephant in the room is whether the observed treatment effects from short-term trials persist over time. The investigators projected promising outcomes under the assumptions that such benefits persist, but this per se does not support the existence of such long-term effects. Second, the investigators worked with average parameter values for exacerbations and lung function changes. Due to non-linearities in associations, working with the “average value” of parameters may not properly reflect patterns that represent those of the average COPD population. Third, the investigators [18] modelled a rapid increase in exacerbation frequencies over time (from 0.5 to 3.0 events per year over 4 years), which may not be accurate. For example, in both the ECLIPSE and SPIROMICS cohorts, the underlying exacerbation rates were stable for 3 years [20]. On a broader scale, complex modelling efforts of this type that are based on data from multiple different sources must be subjected to extensive validation. In particular, external validation, the ability of the model to replicate patterns in the data that are not used as inputs into the model, is crucial in establishing the credibility of projections. An example of a validated model is EPIC, which has recently been used to answer a similar question [21].

Where does this leave us? First, it is crucial to realise that the benefits of triple therapy were additive over time in this modelling study. Most patients who start triple therapy are currently well past the age of 50 years (the age at which triple therapy was initiated in DEPICT-2), and as such might not have enough time to accrue a similar extent of benefit as modelled in this study. Nevertheless, based on the results of Singh et al. [18] and others [8, 9, 12, 21] (figure 1), we suggest the earlier use of triple therapy in the disease course of COPD patients than is presently recommended by traditional COPD guidelines [6, 22]. However, additional clinical and economic evaluations will be needed to determine the exact severity at which this treatment should be commenced in these patients. Moreover, given that inhalers, especially those that contain propellants (e.g. metered-dose inhalers), release greenhouse gases, assessment of the environmental impact of using triple therapy earlier in the course of disease is also required before implementation [23]. Second, we discourage the use of LABA/LAMAs or triple therapy in patients without airflow limitation on spirometry, as they are likely to be ineffective [24]. Third, we encourage future studies to understand the fundamental mechanisms by which triple or dual therapies can modify COPD over time. We also advocate for more detailed modelling studies, which incorporate modelling disease and treatment effect heterogeneity, the effects of smoking cessation, improved air quality and better management of comorbidities, which are common in elderly COPD patients. Ultimately, we believe that the field will benefit from a risk-based approach towards disease management. Similar to the use of statins based on individuals’ risk for cardiovascular disease, we believe explicit elicitation of risk (e.g. for long-term lung function decline, exacerbations and mortality) [25, 26] into the decision-making process for the long-term use of triple and other therapies will improve the efficiency of medical decisions and enable a more personalised approach to preventive therapies in COPD.

FIGURE 1.

The potential mechanisms by which inhaled triple therapy may modify the course of COPD over time. Inhaled triple therapy containing an inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist has been shown to improve lung function, reduce exacerbations, lower mortality and prevent cardiovascular events in patients with moderate-to-severe COPD over 1 year [11, 12]. If these benefits remain resilient across decades of therapy, according to DEPICT-2, dual or triple therapy can significantly modify the natural course of COPD and reduce its burden of disease.