Individualize COPD Pharmacologic Treatment Regimens

Chronic obstructive pulmonary disease (COPD), which has variable severity, is preventable and treatable.

COPD primarily affects smokers over age 40 and is a leading cause of mortality worldwide and is predicted to be the third-leading cause of death by 2020.¹Prevalence is estimated at 4% to 10% worldwide and about 6.4 % in the United States. In the primary-care setting, about 50% of patients with severe COPD remain undiagnosed. The global burden of COPD is expected to increase, because of continued exposure to COPD risk factors, as well as the aging population.²COPD is characterized by chronic and progressive core symptoms of cough with or without sputum production and dyspnea. The airflow limitation in COPD is caused by a combination of parenchymal destruction (emphysema) and small airway disease (obstructive bronchiolitis). Treatment modalities are guided by disease severity, and goals should focus on decreasing exacerbations, improving quality of life, preventing hospitalizations, and reducing symptoms.^3,4Concomitant comorbidities in patients with COPD also affect hospitalizations and outcome and should be treated appropriately. None of the current medications modify disease progression, which is the hallmark of COPD.

Pharmacotherapeutics

Obstructive lung disease is characterized by a FEV1/FVC ratio of less than 0.70. Patients with COPD have a spirometry classification (grade 1 to 4).⁴The Gold Initiative for Chronic Obstructive Lung Disease system, known as GOLD, also categorizes patients into 4 categories (A,B,C,D), based on core symptoms, including breathlessness, which are assessed using hospitalizations, risk of exacerbations, and standardized questionnaires.⁴

Smoking cessation should be strongly encouraged and supported in patients who continue to smoke. Smoking cessation can be facilitated with non-pharmacologic and pharmacologic modalities. Pharmacotherapy for COPD centers on long- or short-acting bronchodilators, specifically adrenergic agonists, antimuscarinic drugs, and inhaled Beta₂. Comparative efficacy of short-acting beta agonists and short-acting antimuscarinic agents is generally similar with similar tolerability.⁴Types of inhaler devices include dry powder inhalers, metered dose inhalers, nebulizers, and soft mist inhalers. Each delivery device provides similar efficacy, and the key factors in device selection are patient ability to use properly, cost, preference, and treatment setting.⁴

Treatment for patients with COPD is generally based on the category and stage of severity. Patients with COPD in category A are minimally symptomatic and experience fewer than 1 exacerbations per year. These patients are prescribed a short-acting inhaled bronchodilator as needed. Short-acting bronchodilators reduce symptoms, and short-acting inhaled beta₂agonists (albuterol, levalbuterol) can be used as needed, improve symptoms quickly, last for 4 to 6 hours, and modestly improve FEV1.⁴Inhaled short-acting beta₂agonists are generally well tolerated at recommended dosages with an increased heart rate and tremors more common in higher dosages. Short-acting antimuscarinic drugs, such as ipratropium, are usually dosed 3 to 4 times daily and also improve lung function and symptoms. Ipratropium should be used with caution in patients with narrow-angle glaucoma and prostatic hypertrophy.

Category B patients are more symptomatic and have 0 to 1 exacerbations per year. Recommended pharmacotherapy for patients in category B includes daily use of a long-acting bronchodilator, either a long-acting beta₂agonist (LABA) or long-acting inhaled antimuscarinic agents (LAMA), plus an inhaled short-acting bronchodilator as needed. LABAs include aformoterol, formoterol, indacaterol, olodaterol, salmeterol, and vilanterol, which are dosed either once or twice daily. Aformaterol is also available as a solution for nebulization. The LAMAs include aclidinium, glycopyrrolate, revefenacin, tiotropium, and umeclidinium. Both LABAs and LAMAs have similar efficacy for quality of life and symptom control, but LAMA may be more effective at reducing the exacerbation rate. For patients with inadequately controlled symptoms on 1 long-acting bronchodilator, the addition of a long-acting bronchodilator from the other class may improve symptoms.⁴The are conflicting data regarding the potential increase in cardiovascular risk with the initiation of LABAs or LAMAs in patients with COPD.⁵The Understanding Potential Long-Term Impacts on Function with Tiotropium trial and the ASCENT trial provide evidence against significant major adverse cardiovascular events.^5-8

For GOLD Category C patients, first line pharmacotherapy is daily use of LAMAs. Long-acting inhaled antimuscarinic agents include aclinidium bromide, glycopyrronium, tiotropium, and umeclinidium, which are administered once or twice daily. LAMAs reduce the risk of exacerbations and hospitalizations compared with LABAs.⁹

In patients on a LAMA with repeated exacerbations, guidelines recommend the addition of a LABA (preferred) or an inhaled corticosteroid (ICS). LAMA plus LABA combinations are preferred, because they improve lung function and control mild exacerbations with a lower risk of pneumonia compared with ICS.¹⁰

Category D patients have severe symptoms with recurrent exacerbations and hospitalizations. Initiating therapy with a LAMA alone or a LABA/LAMA combination is recommended and has been shown to decrease exacerbations and improve patient outcomes. The use of an ICS has been shown to increase the risk of developing pneumonia in these patients and is therefore not recommended as initial therapy. In patients with asthma/COPD overlap, the ICS/LABA may be the initial choice of therapy.¹⁰Eosinophilia may be used to guide this latter treatment initiative, though this is still under debate.¹⁰In Category D patients who are prescribed a LABA/LAMA combination with persistent exacerbations, it is reasonable to add an ICS or switch to LABA/ICS. However, this regime may not appropriately control exacerbations, and a LAMA may be needed.

There are also a number of pharmacologic considerations in patients using ICS/LABA/LAMA combination therapy who have persistent exacerbations. Oral roflumilast can be added in patients with FEV1 < 50% predicted especially if they have been hospitalized for an exacerbation. Roflumilast is a phosphodiesterase -4 (PDE4) inhibitor that reduces inflammation by inhibiting the breakdown of intracellular cyclic AMP.^11,12It is used once daily as a maintenance oral medication to prevent exacerbations, but it has a modest efficacy on lung function.

Finally, oral azithromycin therapy either daily or 3 times per week can be added for repeated exacerbations despite recommended standard therapy.^13,14

Conclusion

COPD is a chronic, preventable, and treatable disease. The goal of treatment is to improve exercise tolerance and overall health status; prevent disease progression; prevent and treat exacerbations; and reduce symptoms. Smoking cessation should be strongly encouraged and supported for patients with COPD who continue to smoke. In addition, reduction in occupational and personal exposure to fumes, gases, and pollutants should be targeted. It is essential to individualize pharmacologic treatment regimens and provide instruction on the proper use of inhalation devices. Inhaler technique and clinical response should be reassessed at follow-up visits every 3 to 6 months in stable patients before adjusting pharmacological regimens.

References

1. CDC. What is COPD?cdc.gov/copd/index.html. Updated June 6, 2018. Accessed February 20, 2018
2. American Lung Association. Trends in COPD (chronic bronchitis and emphysema): morbidity and mortality.https://www.lung.org/assets/documents/research/copd-trend-report.pdf. Published March 2013. Accessed January 28, 2020.
3. Montuschi P. Pharmacological treatment of chronic obstructive pulmonary disease.Int J Chron Obstruct Pulmon Dis.2006;1(4):409-423.

1. Global initiative for chronic obstructive lung disease. Global Initiative for Chronic Obstructive Lung Disease, Inc website. goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf. Published 2018. Accessed January 28, 2020.
2. Wang MT, Liou JT, Lin CW, et al. Association of cardiovascular risk with inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study.JAMA Intern Med.2018;178(2):229-238. doi: 10.1001/jamainternmed.2017.7720.
3. Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.JAMA.2008;300(12):1439-1450. doi: 10.1001/jama.300.12.1439.
4. Tashkin D, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease (UPLIFT trial).Rev Port Pneumol.2009;15(1);137-140. doi: 10.1016/S0873-2159(15)30121-5.
5. Wise RA, Chapman KR, Scirica BM, et al. Effect of aclidinium bromide on major cardiovascular events and exacerbations in high-risk patients with chronic obstructive pulmonary disease: the ASCENT-COPD randomized clinical trial.JAMA.2019;321(17):1693-1701. doi: 10.1001/jama.2019.4973.
6. Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease.Cochrane Database Syst Rev.2012;(9):CD009157. doi: 10.1002/14651858.CD009157.pub2.
7. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol-blycopyrronium versus salmeterol-fluticasone for COPD.N Engl J Med.2016;374(23):2222. doi: 10.1056/NEJMoa1516385.
8. Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial.Lancet.2015;385(9971):857-66. doi: 10.1016/S0140-6736(14)62410-7.
9. Rabe KF. Update on roflumilast, a phosphodiesterase 4 inhibitor for the treatment of chronic obstructive pulmonary disease.Br J Pharmacol.2011;163(1):53-67. doi: 10.1111/j.1476-5381.2011.01218.x.
10. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD.N Engl J Med.2011;365(8):689-98.

11. Herath SC, Normansell R, Maisey S, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD).Cochrane Database Syst Rev.2018;10:CD009764.