Pharmacologic Therapies for Preventing Chronic Obstructive Pulmonary Disease Exacerbations: A Comprehensive Review
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Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder characterized by acute exacerbations that accelerate disease progression, increase hospitalizations, and elevate mortality. Effective management focuses on preventing these exacerbations owing to their significant impact on long-term outcomes. This review compiles current evidence regarding pharmacologic interventions aimed at reducing exacerbations, which include inhaled therapies, oral treatments, and novel agents. Established inhaled agents, such as long-acting beta-agonists, long-acting muscarinic antagonists, and combinations of inhaled corticosteroids, are fundamental, with the personalized selection based on patient-specific factors like blood eosinophil levels and history of exacerbations. Oral treatments, including roflumilast and azithromycin, confer additional benefits for patients with particular characteristics, such as chronic bronchitis or frequent exacerbations. Roflumilast effectively reduces exacerbations as a phosphodiesterase 4 (PDE-4) inhibitor in conjunction with inhaled therapies, while azithromycin provides anti-inflammatory and antimicrobial properties, particularly advantageous for elderly former smokers. Innovative therapies such as ensifentrine, a dual PDE-3/4 inhibitor, and dupilumab, which targets type 2 inflammation, demonstrate potential for lowering exacerbations in specific subgroups. This body of evidence endorses a personalized, phenotype-driven approach to COPD management, aimed at optimizing therapeutic strategies to decrease exacerbation frequency and enhance patient outcomes.
Introduction
Chronic obstructive pulmonary disease (COPD) is a progressively worsening respiratory condition characterized by persistent airflow limitation and debilitating symptoms. A fundamental goal in COPD management is the prevention of acute exacerbations, which are often defined as episodes of deteriorating respiratory symptoms necessitating additional treatments [1]. Marked by increased dyspnea, sputum volume, and sputum purulence, exacerbations are typically triggered by respiratory infections or environmental pollutants [2,3]. The frequency and severity of acute exacerbations among COPD patients vary, influenced by heterogeneous disease phenotypes, endotypes, and comorbidities [4]. Acute exacerbations significantly contribute to a poor prognosis in COPD [5]. Given the impact of exacerbations on the clinical course of COPD, effective long-term management should prioritize interventions that mitigate the risk of future exacerbations.
Pharmacologic interventions have played a crucial role in preventing acute exacerbations of COPD. Pharmacologic therapies help reduce the rates of exacerbations, slow disease progression, and enhance long-term outcomes [6,7]. This review provides an evidence-based overview of the current landscape of pharmacologic treatments, emphasizing effective strategies for preventing COPD exacerbations.
Clinical Significance of Acute Exacerbations
The relationship between exacerbations and mortality has been well-documented across multiple cohort studies. Severe exacerbations, necessitating hospitalization, significantly elevate the risks of both subsequent exacerbations and mortality. In a large cohort study involving 73,106 COPD patients, of whom 50,580 died over a 17-year follow-up, mortality rates peaked immediately following a severe exacerbation, especially within the first week after hospital discharge [8]. Notably, patients who undergo multiple hospitalizations due to severe exacerbations demonstrate significantly poorer outcomes [8,9]. In 2010, it was reported that 33% of patients hospitalized for acute exacerbations succumbed within 6 months, and 50% within 2 years [5]. Despite advancements in COPD treatment, more than half of the patients succumb within 4 to 8 years following a severe exacerbation [8,10].
Assessment of Acute Exacerbations
Evaluating the frequency and severity of exacerbations is essential for understanding their potential impact on patient outcomes. Frequent exacerbations hasten disease progression, diminish quality of life, restrict physical activity, increase hospital admissions, and heighten mortality risk [5,11]. Furthermore, exacerbation frequency is a robust predictor of future episodes, establishing a vicious cycle wherein patients experiencing frequent exacerbations are more likely to endure recurrent events. The incidence of exacerbations escalates among patients undergoing frequent severe exacerbations that necessitate hospitalization [5,8].
The impact of exacerbations on COPD prognosis varies depending on their severity. Severe exacerbations particularly increase the future risk of exacerbations and consequently elevate mortality risk compared to moderate exacerbations [9,10]. A higher frequency of severe exacerbations is associated with a significantly increased risk of long-term complications, such as repeated hospitalizations and elevated mortality rates [8]. Exacerbations of COPD have been categorized into three levels of severity.
(1) Mild exacerbations: These occur when the symptoms are managed solely with inhaled short-acting bronchodilators.
(2) Moderate exacerbations: These require treatment with antibiotics, systemic corticosteroids, or both.
(3) Severe exacerbations: These lead to emergency room visits or hospital admissions due to symptom severity.
Pharmacologic Treatments for Reducing Exacerbations via Inhalation
Major studies on inhaled pharmacologic treatments are summarized in Figure 1.
Summary of major studies on inhaled pharmacologic treatments for acute exacerbation. *Clinical trials had acute exacerbation as the primary outcome. LABA: long-acting beta-agonist; LAMA: long-acting muscarinic antagonist; ICS: inhaled corticosteroid; PBO: placebo.
1. Long-acting beta-agonists
Long-acting beta-agonists (LABAs) reportedly reduce COPD exacerbations by promoting bronchodilation via sustained activation of β2-adrenergic receptors, improving airflow and reducing inflammation. The efficacy of LABAs in decreasing exacerbations has been corroborated by several pivotal studies. The TORCH trial (2007) enrolled patients aged over 40 years with a smoking history of at least 10 pack-years and a forced expiratory volume in 1 second (FEV1) <60%, and compared the effects of salmeterol, fluticasone propionate, and their combination against placebo [12]. The primary outcome was mortality over 3 years, with secondary outcomes that focused on exacerbations. Salmeterol alone decreased moderate-to-severe exacerbations by 15% and severe exacerbations by 18%. Likewise, the SUMMIT trial (2016) assessed fluticasone furoate and vilanterol in patients with an modified Medical Research Council (mMRC) score ≥2 in comparison to placebo [13]. Although mortality was the primary outcome, the secondary outcomes included exacerbations. Vilanterol reduced moderate-to-severe exacerbations by 12% and severe exacerbations by 14%. Furthermore, a network meta-analysis demonstrated that LABAs reduce moderate-to-severe exacerbations by 21% compared to placebo, reinforcing LABAs as an effective intervention for exacerbation prevention [14].
2. Long-acting muscarinic antagonists
Long-acting muscarinic antagonists (LAMAs) are recognized for their role in preventing COPD exacerbations primarily through the inhibition of M3 muscarinic receptors, which mitigates bronchial smooth muscle contraction and enhances bronchodilation. A pivotal study on LAMAs is the UPLIFT trial (2008), which adopted inclusion criteria akin to those of the TORCH trial, comparing tiotropium with placebo [15]. The primary endpoint was the decline in FEV1 over 4 years, during which tiotropium decreased moderate-to-severe exacerbations by 14% relative to placebo. The Tie-COPD trial (2017) centered on patients with an FEV1 >50%, measuring the change in FEV1 over 2 years as the primary outcome [16]. Baseline characteristics demonstrated that 71% to 75% of participants had a COPD assessment test (CAT) score <10, and over 88% possessed an mMRC score <2, indicating that most were categorized within Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A. This study found that tiotropium decreased the frequency of mild to severe exacerbations by 40% compared to placebo. Subgroup analysis of patients with a CAT score <10 also highlighted significant reductions in moderate-to-severe and severe exacerbations. In a network meta-analysis, LAMAs were shown to reduce moderate-to-severe exacerbations by 36% compared to placebo [14].
3. LAMAs vs. LABAs
One of the pivotal studies comparing LABA and LAMA is the POET-COPD trial (2011), which encompassed patients aged 40 and above with a smoking history of at least 10 pack-years, FEV1 ≤70%, and at least one prior moderate-to-severe exacerbation [17]. This trial assessed tiotropium compared with salmeterol, focusing on time to the first moderate-to-severe exacerbation over 1 year. Tiotropium reduced moderate-to-severe exacerbations by 17% and severe exacerbations by 28% relative to salmeterol, indicating that LAMAs may be more efficacious than LABAs for patients with a history of exacerbations. An equally significant study, the INVIGORATE trial (2013), included patients with lower lung function than those in the POET-COPD trial and assessed tiotropium against indacaterol [18]. The primary outcome was FEV1 improvement at 12 weeks; however, over a year, tiotropium reduced moderate-to-severe exacerbations by 19% compared to indacaterol. In a network meta-analysis, LAMAs significantly reduced moderate-to-severe exacerbations by 15% compared to LABAs [14]. These findings suggest that LAMAs offer superior protection against exacerbations compared to LABAs, particularly in COPD patients with a history of exacerbations.
4. Inhaled corticosteroid/LABAs vs. LABAs
Inhaled corticosteroid (ICS) reduces airway inflammation by inhibiting the expression of inflammatory mediators and cytokines, while LABAs stimulate β2-adrenergic receptors to relax bronchial smooth muscle. The combined use of ICS and LABA is recognized for their synergistic effects, with ICS countering receptor desensitization induced by LABA, and LABA augmenting the delivery of ICS to the airways, thereby enhancing their collective therapeutic efficacy. The TORCH trial (2007) demonstrated that the ICS/LABA combination of fluticasone propionate and salmeterol decreased moderate-to-severe exacerbations by 11% compared to salmeterol alone [12]. Kardos et al. [19] (2007), focusing on COPD patients with FEV1 <50% and a history of two or more moderate-to-severe exacerbations, reported that the combination of salmeterol and fluticasone propionate further reduced the annual exacerbation rate by 34% compared to salmeterol alone. Similarly, in the SUMMIT trial (2016), which included only patients with an mMRC score ≥2, the ICS/LABA combination of fluticasone furoate and vilanterol reduced moderate-to-severe exacerbations by 19% compared to salmeterol alone [13]. Post hoc analyses further confirmed that the advantage of using ICS/LABA to prevent exacerbations was particularly significant in patients with elevated blood eosinophil levels at the onset of the study, compared to those on LABA monotherapy [20-22]. A network meta-analysis also revealed that ICS/LABA significantly reduced moderate-to-severe exacerbations by 17% compared to LABA alone [14]. Therefore, ICS/LABA therapy offers substantial clinical advantages in preventing exacerbations compared to LABA monotherapy, especially in COPD patients with elevated eosinophil counts and a heightened risk of exacerbations.
5. ICS/LABAs vs. LAMAs
Both LAMAs and ICS/LABAs have been shown to effectively reduce exacerbations compared to LABAs alone; however, it remains uncertain which treatment is superior in preventing exacerbations. The INSPIRE trial (2008) evaluated fluticasone propionate/salmeterol, which demonstrated superiority over salmeterol alone in the TORCH trial, against tiotropium, which also surpassed salmeterol in the POET-COPD trial, in patients with a history of exacerbations and an mMRC score of ≥2 [23]. The primary outcome was moderate-to-severe exacerbations over a year. The rate ratio for these exacerbations was 0.97, indicating no significant difference between fluticasone propionate/salmeterol and tiotropium in terms of exacerbation prevention. Interestingly, fluticasone propionate/salmeterol was more effective in reducing steroid-requiring exacerbations, while tiotropium more effectively reduced antibiotic-requiring exacerbations. Though there was no statistically significant difference in severe exacerbations, tiotropium exhibited a trend toward a lower rate of severe exacerbations. A cohort study suggested that ICS/LABA combinations could be more effective than LAMA in reducing moderate-to-severe exacerbations in COPD patients with elevated blood eosinophil levels (>4%) [24]. Determining whether ICS/LABA or LAMA is more effective may therefore depend on individual phenotypic or endotypic characteristics such as blood eosinophil profiles.
6. LABA/LAMAs vs. LAMAs
LABAs activate β2-adrenergic receptors to relax bronchial smooth muscle, while LAMAs inhibit the action of M3 muscarinic receptors, thereby preventing bronchial smooth muscle contraction. The synergistic combination of these two agents facilitates bronchodilation through divergent mechanisms, markedly reducing airway inflammation and effectively mitigating airflow limitation and air trapping. The SPARK trial (2013) recruited patients with a history of moderate-to-severe exacerbations, comparing the efficacy of indacaterol/glycopyrronium, tiotropium, and glycopyrronium over 64 weeks, focusing on exacerbations as the primary endpoint [25]. The results demonstrated that the indacaterol/glycopyrronium combination reduced the rate of moderate-to-severe exacerbations by 12% compared to glycopyrronium alone, but showed no significant reduction in severe exacerbations. A pairwise meta-analysis indicated that LABA/LAMA usage decreased moderate-to-severe exacerbations by 16% relative to LAMA [26]. However, a network meta-analysis revealed no significant reduction in moderate-to-severe exacerbations, although it suggested an 8% reduction in exacerbations ranging from mild to severe with LABA/LAMA compared to LAMA [14]. The discrepancies in findings may be attributed to differences in the exacerbation histories of the studied patient populations.
Indeed, studies enrolling patients without specific consideration of exacerbation history failed to show a greater reduction in exacerbations with LABA/LAMA compared to LAMA alone. For instance, the ACLIFORM-COPD trial (2014) demonstrated that aclidinium/formoterol did not significantly lower the rate of moderate-to-severe exacerbations in comparison to aclidinium alone [27]. Similarly, the TONADO trial (2015) compared the effects of the olodaterol/tiotropium combination with those of olodaterol and tiotropium as monotherapies [28]. The combination of olodaterol 5 μg and tiotropium 2.5 μg was more effective in reducing exacerbations than either monotherapy alone, but the marketed doses of olodaterol 5 μg and tiotropium 5 μg did not achieve a significant reduction in exacerbations compared to tiotropium alone.
To address the differential effects of LABA/LAMA and LAMA in patients with a history of exacerbations, the DYNAGITO trial (2018), building on the TONADO trial, concentrated on COPD patients with prior exacerbations, comparing the combination of tiotropium 5 μg and olodaterol 5 μg with tiotropium monotherapy over 52 weeks [29]. Results indicated that the combination therapy reduced the incidence of moderate-to-severe exacerbations by 7%. However, echoing the SPARK trial, there was no significant difference in the incidence of severe exacerbations between the LABA/LAMA and LAMA monotherapy. These findings underscore that while LABA/LAMA is more effective than LAMA alone in mitigating moderate-to-severe exacerbations in COPD patients with an exacerbation history, its efficacy in preventing severe exacerbations remains limited.
7. Comparing LABA/LAMAs vs. ICS/LABAs
The LANTERN trial (2015) compared indacaterol/glycopyrronium with fluticasone propionate/salmeterol in patients with FEV1 30% to 70% and an mMRC score ≥2, regardless of exacerbation history, over a period of 26 weeks, making trough FEV1 the primary outcome [30]. The study demonstrated that indacaterol/glycopyrronium led to a significant 35% reduction in the risk of exacerbations compared to fluticasone propionate/salmeterol. Similarly, the FLAME trial (2016) evaluated indacaterol/glycopyrronium against fluticasone propionate/salmeterol in patients with a history of exacerbations and an mMRC score ≥2, designating moderate-to-severe exacerbations as the primary endpoint over 52 weeks [31]. Indacaterol/glycopyrronium was shown to significantly reduce moderate-to-severe exacerbations by 22% and severe exacerbations by 19% compared to fluticasone propionate/salmeterol. A meta-analysis corroborated these outcomes, confirming that LABA/LAMA reduced the moderate/severe exacerbation rate by 18% compared to ICS/LABA [32].
Real-world cohort studies have not indicated a significant difference between LABA/LAMA and ICS/LABA in mitigating moderate-to-severe exacerbations [33]. Furthermore, previous network meta-analyses have failed to establish a discernible advantage for either LABA/LAMA or ICS/LABA in reducing exacerbations [14,34]. These divergent outcomes could be attributed to variations in baseline ICS usage or blood eosinophil counts (BEC) [35]. For instance, in the LANTERN trial, 54% of patients were using ICS at baseline, while in the FLAME trial, this figure was 75%. Contrarily, the ILLUMINATE trial (2013), which did not report significant differences in safety outcomes such as worsening of COPD between indacaterol/glycopyrronium and fluticasone propionate/salmeterol, had only 35% of participants using ICS at baseline [36]. Most notably, post hoc analyses from the IMPACT and ETHOS trials demonstrated that the efficacy of ICS/LABA vs. LABA/LAMA differs depending on BECs [37,38]. Specifically, LABA/LAMA tends to be more effective for patients with lower BECs, whereas ICS/LABA exhibits greater efficacy in those with higher BECs.
8. ICS/LABA/LAMAs vs. LABA/LAMAs
ICS/LABA/LAMA or triple therapy diminishes airway inflammation by suppressing inflammatory mediator expression via ICS, relaxes bronchial smooth muscle through LABA-mediated activation of β2-adrenergic receptors, and inhibits bronchial smooth muscle contraction by antagonizing M3 muscarinic receptors with LAMA. ICS augments the effects of LABA and LAMA by alleviating airway obstruction and diminishing excessive airway resistance, while the combination of LABA and LAMA prevents receptor desensitization and maximizes airflow enhancement, thereby considerably lowering the risk of COPD exacerbations. The TRIBUTE trial (2018) was conducted under conditions analogous to those of the FLAME trial, enrolling symptomatic patients with a CAT score ≥10 and a history of acute exacerbations [39]. The TRIBUTE trial assessed the efficacy of indacaterol/glycopyrronium, which proved to be more effective in reducing moderate-to-severe exacerbations in the FLAME trial, compared to beclomethasone/formoterol/glycopyrronium. The primary endpoint was the frequency of moderate-to-severe acute exacerbations over 52 weeks. The research indicated that beclomethasone/formoterol/glycopyrronium decreased moderate-to-severe exacerbations by 15% relative to indacaterol/glycopyrronium. However, there was no statistically significant difference between the two treatments in terms of reducing severe exacerbations.
Similarly, the IMPACT trial (2018) was conducted in a setting similar to that of the TRIBUTE trial, but it utilized slightly different criteria for exacerbation history based on FEV1 levels [40]. It also included symptomatic patients with a CAT score ≥10. The trial compared fluticasone furoate/umeclidinium/vilanterol with fluticasone furoate/vilanterol and umeclidinium/vilanterol. The primary outcome was the rate of moderate-to-severe exacerbations over 52 weeks. Results indicated that fluticasone furoate/umeclidinium/vilanterol reduced moderate-to-severe exacerbations by 25% and severe exacerbations by 34% compared to umeclidinium/ vilanterol. A post hoc analysis of the IMPACT trial revealed that the efficacy of fluticasone furoate/umeclidinium/vilanterol in reducing moderate and severe exacerbations increased with higher blood eosinophil levels [37]. These findings emphasize the significance of considering BEC when optimizing COPD treatment strategies.
The ETHOS trial (2020), conducted in a context similar to the IMPACT trial, examined the efficacy of budesonide 320 and 160 μg in combination with formoterol/glycopyrronium versus budesonide (320 μg)/formoterol and formoterol/glycopyrronium [41]. The primary endpoint was the frequency of moderate-to-severe acute exacerbations over a 52-week period. The findings indicated that, irrespective of the dosage, budesonide (320 μg)/formoterol/glycopyrronium significantly enhanced outcomes, reducing moderate-to-severe exacerbations by approximately 24% compared to formoterol/glycopyrronium alone. Nevertheless, there was no significant difference between budesonide/formoterol/glycopyrronium and formoterol/glycopyrronium in the reduction of severe exacerbations. Consistent with observations from the IMPACT trial, a post hoc analysis of the ETHOS trial suggested that budesonide/formoterol/glycopyrronium more effectively reduced moderate-to-severe exacerbations than formoterol/glycopyrronium among patients with a BEC ≥100 [38].
Since the 2023 GOLD report, consensus recommendations from experts have underscored the importance of combining ICS with LABA/LAMA in distinct patient subgroups, as evidenced by post hoc analyses of the IMPACT and ETHOS trials. For patients who have experienced at least two moderate exacerbations or one severe exacerbation, and a BEC ≥300 cells/µL, the integration of ICS with LABA/LAMA therapy is recommended to optimize the prevention of exacerbations. Additionally, for patients already on LABA/LAMA therapy who continue to face exacerbations, the addition of ICS is advocated when the BEC is ≥100 cells/µL. These recommendations emphasize the emerging role of BEC as a critical biomarker for guiding therapeutic adjustments, thereby enabling more precise and efficacious management of COPD.
Triple therapy may be less effective for COPD patients who continue smoking. A post hoc analysis of the IMPACT trial showed that former smokers experienced a more significant reduction in exacerbations with triple therapy compared to current smokers [37]. Smoking may diminish the effectiveness of ICS in COPD due to induced ‘steroid resistance.’ This effect has been documented in various clinical trials and is believed to arise from the oxidative stress induced by cigarette smoke, which deactivates histone deacetylase-2, an essential enzyme in the anti-inflammatory action of ICS [42]. However, in the subgroup analysis of the TRIBUTE trial, triple therapy was more efficacious in current smokers [39], and a post hoc analysis of the ETHOS trial demonstrated no significant differences in the efficacy of triple therapy between current and former smokers [43]. Consequently, there is inadequate evidence to recommend the selection of triple therapy based solely on smoking status in clinical settings.
Oral Pharmacologic Treatments for Reducing Exacerbations
1. Roflumilast
Roflumilast reduces bronchial inflammation by selectively inhibiting phosphodiesterase 4 (PDE-4), thereby suppressing the production of pro-inflammatory cytokines and diminishing the activation of inflammatory cells. The M2-124 and M2-125 trials (2009) evaluated the efficacy of oral roflumilast (500 μg once daily) in comparison to placebo in COPD patients who were current or former smokers with ≥20 pack-years, aged over 40 years, suffering from chronic bronchitis, with an FEV1 <50%, and a history of exacerbations [44]. Over the 52-week study period, the primary outcomes were changes in FEV1 and the rate of moderate-to-severe exacerbations. The results demonstrated that roflumilast reduced the rate of moderate-to-severe exacerbations by 17%. However, a significant limitation of this study was the exclusion of ICS and LAMA, and the use of LABAs only in half of the patients, with the remainder receiving only short-acting bronchodilators, following clinical guidelines of that period.
To address these limitations, the REACT trial (2015) was conducted to evaluate the supplemental benefit of roflumilast when used alongside ICS/LABA [45]. This study enrolled COPD patients with chronic bronchitis, FEV1 <50%, and a history of ≥2 exacerbations, assessing the rate of moderate-to-severe exacerbations as the primary outcome over 1 year. The results indicated that the addition of roflumilast to ICS/LABA reduced the rate of moderate-to-severe exacerbations by an additional 13%.
Likewise, the RE2 SPOND trial (2016), which had inclusion criteria similar to the REACT trial, explored the effect of roflumilast on the prevention of exacerbations [46]. Notably, 42% of patients were on triple therapy at enrollment. Nevertheless, this clinical trial did not demonstrate a significant reduction in moderate-to-severe exacerbations with roflumilast. However, subgroup analysis revealed that in patients with a history of >3 moderate or ≥1 severe exacerbation in the previous year, roflumilast provided a significant additional benefits in reducing exacerbation rates when added to ICS/ LABA.
Thus, roflumilast has demonstrated efficacy in reducing exacerbations, particularly when used as an adjunct to ICS/LABA in severe to very severe COPD patients with chronic bronchitis and a history of exacerbations. However, there is a scarcity of clinical trials specifically investigating the benefits of adding roflumilast to LABA/LAMA or triple therapy. Recent real-world data indicate a potential additional benefit of roflumilast when used in combination with not only ICS/LABA but also LABA/LAMA or triple therapy [47]. In this study, with a median observation period of 2 years, the use of roflumilast was associated with a reduced adjusted hazard ratio for moderate-to-severe exacerbations by 21% in mono-bronchodilator users, 41% in ICS/LABA users, 20% in LABA/LAMA users, and 43% in ICS/LABA/LAMA users. Notably, a significant benefit of roflumilast was observed with treatment durations of ≥3 months. Thus, the efficacy of roflumilast in patients using triple therapy is expected to be comparable to that observed in ICS/LABA users, while the effect size in LABA/LAMA users may be lower than that in ICS/LABA users.
2. Azithromycin
Azithromycin is known to reduce COPD exacerbations by exerting anti-inflammatory and immunomodulatory effects, inhibiting neutrophil activation, and suppressing the release of pro-inflammatory cytokines, while also preventing respiratory infections and attenuating exacerbation triggers. Albert et al. [48] (2011) assessed the efficacy of azithromycin (250 mg daily for 1 year) in reducing exacerbation events in patients with COPD. Participants eligible for this study had a smoking history of at least 10 pack-years, an FEV1 less than 70%, and at least one exacerbation in the preceding year. The primary outcome was the rate of moderate-to-severe exacerbations. Azithromycin significantly reduced moderate-to-severe exacerbations by 27% compared to placebo. However, no significant difference was observed in the rate of severe exacerbations. Subgroup analysis revealed that azithromycin was more effective in patients over 65 years old, ex-smokers, and those not using ICS. Nevertheless, the study also noted an increase in colonization with macrolide-resistant organisms and a higher incidence of hearing loss as adverse events.
Han et al. [49] (2014) further examined the efficacy of azithromycin in COPD patients with a history of long-term oxygen therapy or prior exacerbations. Azithromycin was particularly effective in reducing exacerbations requiring both antibiotics and steroids by 24%, although this benefit was not statistically significant after adjusting for confounding factors. Subgroup analysis revealed that azithromycin’s efficacy was enhanced in patients with milder GOLD stages, ex-smokers, and those aged over 65 years.
Therefore, azithromycin may serve as an effective preventive treatment for reducing the risk of future exacerbations, particularly among elderly ex-smokers. Nevertheless, clinicians should monitor for potential adverse effects, such as QTc prolongation, hearing loss, and antibiotic resistance.
3. Muco-active agents
Muco-active agents are known to reduce the risk of COPD exacerbations by regulating mucus secretion, decreasing mucus viscosity, and promoting mucus clearance in the airways. They also exert antioxidant and anti-inflammatory effects, which contribute to the reduction of inflammatory mediators and oxidative stress. The Bronchitis Randomized on NAC Cost-Utility Study (BRONCUS) trial (2005) assessed the effectiveness of N-acetylcysteine at a dosage of 600 mg daily in COPD patients with a history of at least two exacerbations per year and an FEV1 ranging from 40% to 70% [50]. No significant decrease in the frequency of exacerbations was demonstrated in this study with the use of N-acetylcysteine. In contrast, the HIACE trial (2013) reported a 44% reduction in mild to moderate exacerbations, although no significant improvement was observed in severe exacerbations [51]. This study evaluated high-dose N-acetylcysteine (600 mg twice daily) compared to placebo in COPD patients aged 50 years and older, focusing primarily on small airway function parameters. Similarly, the PANTHEON trial (2014) investigated the effects of N-acetylcysteine (600 mg twice daily for 1 year) in COPD patients with an FEV1 between 30% and 70% and a history of at least two exacerbations in the preceding 2 years [52]. The primary endpoint of this study was the annual exacerbation rate. Treatment with N-acetylcysteine resulted in a 20% reduction in mild to severe exacerbations, yet, in line with the findings of the HIACE trial, no notable impact was observed on severe exacerbations. The therapeutic effectiveness of N-acetylcysteine was more pronounced in ex-smokers and current smokers [53]. A meta-analysis of N-acetylcysteine indicated that a daily dosage of ≥1,200 mg is necessary to effectively prevent exacerbations in patients with COPD [54].
In the PEACE trial (2008), COPD patients with FEV1 levels between 25% and 79% and a history of at least two exacerbations within the preceding 2 years were enrolled, irrespective of their smoking status [55]. They received carbocisteine (500 mg three times daily) over 1 year. The primary endpoint was the frequency of mild to severe exacerbations, with the study reporting a 25% reduction in these exacerbations among the carbocisteine group.
The RESTORE trial (2017) assessed the effectiveness of erdosteine (300 mg twice daily for 1 year) in patients with FEV1 levels ranging from 30% to 70% and a history of at least two exacerbations in the preceding year [56]. The primary outcome focused on mild to severe exacerbation rates. The findings indicated a 19% reduction in these exacerbations with erdosteine, although no significant differences were observed in moderate-to-severe exacerbations.
Emerging Pharmacologic Treatments for Reducing Exacerbations
1. Ensifentrine
While roflumilast functions as a selective PDE-4 inhibitor, ensifentrine operates as a dual PDE-3/4 inhibitor, offering a unique mode of action. Inhibition of PDE-4 enhances intracellular cyclic adenosine monophosphate (cAMP) levels within airway cells, resulting in bronchodilation, reduced airway remodeling, and diminished inflammation [57]. Additionally, PDE-4 inhibitors activate inhibitory non-adrenergic noncholinergic nerves, providing a protective effect on the airways [57]. Conversely, inhibition of PDE-3 elevates both cAMP and cyclic guanosine monophosphate levels, predominantly promoting bronchodilation through smooth muscle relaxation [58,59]. This dual inhibition may enhance a broader spectrum of therapeutic effects, addressing both inflammatory and bronchoconstrictive processes in COPD.
The ENHANCE-1 and ENHANCE-2 trials (2023) were phase 3 randomized controlled trials strategically designed to evaluate the efficacy of ensifentrine in managing COPD [60]. ENHANCE-1 was a 24-week study, while ENHANCE-2 extended the evaluation period to 48 weeks. Both trials enrolled COPD patients aged 40 to 80 years with a smoking history of at least 10 pack-years, a post-bronchodilator FEV1 of 30% to 70%, and a mMRC score of ≥2, denoting that the majority of participants were classified as GOLD B.
In these trials, patients were randomized to receive either ensifentrine 3 mg twice daily through a standard jet nebulizer or a placebo. The primary endpoint was the change in FEV1 at 12 weeks. Ensifentrine notably improved FEV1 compared to placebo at 12 weeks, demonstrating significant enhancements in both peak and trough FEV1. Furthermore, ensifentrine significantly reduced the rate of moderate-to-severe exacerbations at 24 weeks, with a similar trend observed at 48 weeks, suggesting a prolonged benefit in exacerbation prevention over time. The analysis of the time to first exacerbation further affirmed the substantial clinical advantage of ensifentrine in reducing exacerbation risk.
Despite potential concerns regarding increased upper respiratory tract infections or respiratory symptoms resulting from direct inhalation of ensifentrine, the clinical trials did not show a higher incidence of such adverse events in the ensifentrine group compared to the placebo group. This outcome underscores the safety and tolerability of ensifentrine, affirming its potential as a promising therapeutic option in the dynamic field of COPD management.
2. Dupilumab
Interleukin 13 (IL-13) primarily contributes to goblet cell hyperplasia, smooth muscle fibroblast activation, and macrophage activation, while IL-4 predominantly stimulates B cells and eosinophils [61]. Both cytokines share a common receptor, IL-4Rα, which mediates their biological effects [62]. Consequently, dupilumab, an anti-IL-4Rα monoclonal antibody, effectively blocks the actions of both IL-4 and IL-13, suppressing type 2 inflammation and presenting a promising therapeutic approach for COPD characterized by type 2 inflammation.
The BOREAS trial (2023) and NOTUS trial (2024) evaluated COPD patients aged 40 to 80 years with a smoking history of at least 10 pack-years, FEV1 <80%, mMRC ≥2, and chronic bronchitis, who were receiving ICS/LABA/LAMA therapy [63,64]. Eligible participants also had a BEC ≥300 cells/µL and a history of at least two moderate or one severe exacerbation in the previous year. Notably, patients with a history of asthma were excluded.
Participants received dupilumab 300 mg subcutaneously every 2 weeks or placebo, and the primary outcome was the rate of moderate-to-severe exacerbations. Dupilumab led to a significant reduction in moderate-to-severe exacerbations by 30% to 34% compared to placebo. Time-to-event analysis also demonstrated a significant reduction in the risk of exacerbation in the dupilumab group. Furthermore, dupilumab significantly improved FEV1, as well as scores on the St. George’s Respiratory Questionnaire (SGRQ) and the Evaluating Respiratory Symptoms in COPD (E-RSCOPD) score, markedly impacting patient-reported symptoms, exacerbations, and lung function.
Conclusion
The prevention of acute exacerbations remains a cornerstone of COPD management due to their profound impact on disease progression, healthcare utilization, and mortality. Established pharmacologic strategies, including bronchodilators and combination therapies, have demonstrated efficacy in decreasing the frequency of exacerbations and enhancing clinical outcomes. Optimizing COPD management should involve personalized therapy selection based on exacerbation history, symptom severity, and BEC to maximize clinical benefits. Ensifentrine, a dual PDE-3/4 inhibitor, has shown significant efficacy in reducing exacerbations through its bronchodilatory and anti-inflammatory effects, offering an additional therapeutic option for COPD management. Dupilumab offers promising potential for reducing exacerbations in specific COPD phenotypes associated with type 2 inflammation.
Notes
Conflicts of Interest
Hyun Woo Lee is an early career editorial board member of the journal, but he was not involved in the peer reviewer selection, evaluation, or decision process of this article. No other potential conflicts of interest relevant to this article were reported.
Funding
No funding to declare.