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“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.
Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.
She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).
On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO2 of 63 mm Hg, and PaCO2 of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.
Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV1 = 40% predicted, FVC = 61% predicted, FEV1/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.
In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.1 She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.
So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?
In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.2 The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.
Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.2 The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.
In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.
In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).3 Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.
Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.4 The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.
On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,5 the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,6 and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β2-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.
There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.7 The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.8 Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.
Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.
References:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/
2. US Food and Drug Administration (Daliresp®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf
3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.
4. US Food and Drug Administration (Zithromyax®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.
6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.
7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.
8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.
“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.
Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.
She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).
On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO2 of 63 mm Hg, and PaCO2 of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.
Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV1 = 40% predicted, FVC = 61% predicted, FEV1/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.
In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.1 She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.
So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?
In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.2 The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.
Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.2 The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.
In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.
In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).3 Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.
Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.4 The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.
On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,5 the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,6 and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β2-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.
There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.7 The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.8 Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.
Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.
References:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/
2. US Food and Drug Administration (Daliresp®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf
3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.
4. US Food and Drug Administration (Zithromyax®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.
6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.
7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.
8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.
“Janice Turner” (name changed to protect confidentiality) is a 66-year-old woman with a 40-pack per year history of smoking. She is very worried about having another COPD exacerbation and wants to know if there are additional medications she could try.
Over the past 2 weeks, her respiratory symptoms have improved and returned to her baseline. She has a daily cough with white phlegm on most days and dyspnea on exertion at one-half block on level ground. She reports using her medications as prescribed and is enrolled in a pulmonary rehabilitation program, which she attends twice per week. She uses 2 to 4 inhalations of albuterol each day.
She is on the following regimen for her COPD, which is unchanged compared with what she has been prescribed for the past 12 months: 1) combination inhaled fluticasone furoate, umeclidinium, and vilanterol via the Ellipta® device, one actuation once daily and 2) inhaled albuterol, two puffs as needed every 4 hours via metered dose inhaler. She demonstrates mastery of inhaler technique for both inhaled devices. Her vaccinations are current (pneumococcus, influenza, respiratory syncytial virus, and COVID-19).
On examination, she can complete sentences without respiratory difficulty, and her vital signs are normal. She has decreased breath sounds in all lung fields, with occasional rhonchi. Heart sounds are distant, but regular, at 92 beats per minute, and she has no peripheral edema. Arterial blood gas at rest on room air indicates a pH of 7.38, PaO2 of 63 mm Hg, and PaCO2 of 42 mm Hg. An electrocardiogram shows sinus rhythm and a QTc interval of 420 milliseconds.
Three months ago, when she was clinically stable, you obtained spirometry, a complete blood count with differential, and a chest radiograph to exclude alternate diagnoses for her ongoing respiratory symptoms. She had severe airflow limitation (post-bronchodilator FEV1 = 40% predicted, FVC = 61% predicted, FEV1/FVC = 65%). At the time, she also had peripheral eosinophilia (eosinophil count of 350 cells/μL) and hyperinflation without parenchymal infiltrates.
In summary, Ms. Turner has severe smoking-associated COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3E and chronic bronchitis with two severe exacerbations in the past 12 months.1 She is currently prescribed triple inhaled maintenance therapy with corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. She has a normal QTc interval.
So what would you recommend to reduce Ms. Turner’s risk of future exacerbations?
In 2011, the US Food and Drug Administration (FDA) approved roflumilast 500 mcg by mouth per day, a selective phosphodiesterase 4 (PDE4) inhibitor, as maintenance therapy to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis.2 The FDA approval was based on a review of the efficacy and safety of roflumilast in eight randomized, double-blind, controlled clinical trials in 9,394 adults with COPD.
Two subsequently completed randomized clinical trials in 2015 (REACT, 1,945 adults) and 2016 (RE2SPOND, 2,354 adults) also found that maintenance oral treatment escalation with roflumilast significantly reduced the risk of COPD exacerbations compared with placebo.2 The most common adverse effects reported with long-term use of roflumilast are related to the gastrointestinal tract (diarrhea, nausea, decreased appetite), weight loss, and insomnia. Four weeks of roflumilast at 250 mcg per day prior to dose escalation to 500 mcg per day reduces the risk of treatment discontinuation and improves tolerability compared with initiating treatment with the maintenance dose.
In 2022, the FDA approved a generic version of roflumilast, providing an opportunity for patients to use roflumilast at a lower cost than was previously possible. Importantly, the FDA Prescribing Information includes a warning to avoid the use of roflumilast in patients being treated with strong cytochrome P450 enzyme inducers (eg, rifampin, phenytoin). The FDA Prescribing Information also recommends weighing the risks and benefits of roflumilast in patients with a history of depression or suicidal thoughts or behavior, or patients with unexplained or clinically significant weight loss.
In 2011 (the same year as the FDA approval of roflumilast), the National Institutes of Health/National Heart, Lung, and Blood Institute-funded COPD Clinical Research Network reported that maintenance treatment with azithromycin reduced the risk of COPD exacerbations compared with placebo in a randomized clinical trial of 1,142 adults with COPD (MACRO study).3 Subgroup analyses indicated that the reduction in the risk of COPD exacerbations with azithromycin was observed in participants with or without chronic bronchitis but not in participants who currently smoked.
Subsequently, two other smaller randomized clinical trials in 2014 (COLUMBUS, 92 participants) and in 2019 (BACE, 301 participants) also demonstrated a reduction in the risk of COPD exacerbations with maintenance azithromycin treatment compared with placebo. Azithromycin can prolong the QT interval and, in rare cases, cause cardiac arrythmias, especially when used with other medications that can prolong the QT interval. There are also concerns that maintenance azithromycin therapy could lead to decrements in hearing or promote the development of macrolide-resistant bacteria. Maintenance treatment with azithromycin to prevent COPD exacerbations is not an FDA-approved indication.4 The FDA approval for azithromycin is currently limited to treatment of patients with mild to moderate infections caused by susceptible bacteria, but it is often prescribed off-label as maintenance treatment for COPD.
On the basis of this body of evidence from clinical trials in COPD, the 2015 CHEST and Canadian Thoracic Society (CTS) guidelines,5 the 2017 European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines,6 and the 2024 GOLD Strategy Report all include recommendations for treatment escalation with maintenance roflumilast or azithromycin to reduce the risk of COPD exacerbations. For example, the 2024 GOLD Strategy Report recommends roflumilast in patients with severe COPD and chronic bronchitis who continue to have exacerbations despite inhaled maintenance treatment with combination long-acting β2-agonist and long-acting muscarinic antagonist or with triple therapy with inhaled corticosteroids, long-acting β2-agonist, and long-acting muscarinic antagonist. An alternative, 2024 GOLD-recommended strategy in this population is maintenance therapy with azithromycin, “preferentially in former smokers.” GOLD’s preference for using azithromycin in patients with smoking history is based on post-hoc (ie, not part of the original study design) subgroup analyses “suggesting lesser benefit in active smokers” in the MACRO study. Results of such analyses have not been reported in other studies.
There are no results from clinical trials that have directly compared the harms and benefits of initiating maintenance therapy with roflumilast or azithromycin in patients with COPD. The roflumilast or azithromycin to prevent COPD exacerbations (RELIANCE; NCT04069312) multicenter clinical trial is addressing this evidence gap.7 The RELIANCE study is funded by the Patient-Centered Outcomes Research Institute and co-led by the COPD Foundation, a not-for-profit organization founded by John W. Walsh, a patient advocate with α1-related COPD. Also, results of two recently completed phase 3 clinical trials with nebulized ensifentrine (ENHANCE-1 and ENHANCE-2), a novel inhibitor of PDE3 and PDE4, were recently published. ENHANCE-1 and ENHANCE-2 studies indicate that twice daily nebulized ensifentrine reduces the risk of COPD exacerbations in patients with moderate or severe COPD.8 Ensifentrine is under review by the FDA, and a decision about its use in the US is expected in the summer of 2024.
Until the results from the RELIANCE clinical trial and the decision by the FDA about ensifentrine are available, we recommended a discussion with Ms. Turner about whether to initiate treatment with maintenance roflumilast or azithromycin. Both can reduce the risk of exacerbations, and the relative benefits and risks of these two evidence-based options are not yet known. Unless Ms. Turner has specific preferences (eg, concerns about specific adverse effects or differences in out-of-pocket cost) in favor of one over the other, she could flip a coin to decide between initiating maintenance roflumilast or azithromycin.
Dr. Krishnan is Professor of Medicine, Division of Pulmonary, Critical Care, Sleep & Allergy, and Professor of Public Health, Division of Epidemiology and Biostatistics, University of Illinois Chicago. Dr. Adrish is Associate Professor, Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston.
References:
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2024 report. https://goldcopd.org/2024-gold-report-2/
2. US Food and Drug Administration (Daliresp®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/022522s003lbl.pdf
3. Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromucin for prevention of exacerbations of COPD. N Engl J Med. 2011;365(8):689-98. PMID: 21864166. doi: 10.1056/NEJMoa1104623.
4. US Food and Drug Administration (Zithromyax®). https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf
5. Criner GJ, Bourbeau J, Diekemper RL, et al. Prevention of acure exacerbations of COPD: American College of Chest Physicians and Canadian Thoracic Society guideline. Chest. 2015;147(4)894-942. PMID: 25321320. doi: 10.1378/chest.14-1676.
6. Wedzicha JA, Calverley PMA, Albert RK, et al. Prevention of COPD exacerbations: a European Respiratory Society/American Thoracic Society guideline. Eur Respir J. 2017;50(3):1602265. PMID: 28889106. doi:10.1183/13993003.02265-2016.
7. Krishnan JA, Albert RK, Rennard SI; RELIANCE study. Waiting for actionable evidence: roflumilast or azithromycin? Chronic Obst Pulm Dis. 2022;9(1):1-3. PMID: 34783231. doi: 10.15326/jcopdf.2021.0272.
8. Anzueto A, Barjaktarevic IZ, Siler TM, et al. Ensifentrine, a novel phospodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE trials). Am J Respir Crit Care Med. 2023;208(4):406-416. PMID: 37364283.