COPD inhaler therapy: A path to success

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COPD inhaler therapy: A path to success

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Michael Arnold, DO, FAAFP

Cate Vordtriede, PharmD, BCPS

Christina Chadwick, DO, MS, ARDMS

Evan Trivette, MD, MMAS

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

Choose the right delivery device and drug while considering patient factors.
Provide patient education through allied health professionals.
Reduce environmental exposures.
Rethink the use of inhaled corticosteroids (ICS).
Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.²Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Considerations in choosing an inhaler device for COPD treatment

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Inhaled pharmacotherapeutic agents for COPD

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) refined ABCD approach to COPD management

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; scalpelandyardstick@gmail.com

References

1. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: 2022 Report. Accessed August 15, 2022. https://goldcopd.org/wp-content/uploads/2021/12/GOLD-REPORT-2022-v1.1-22Nov2021_WMV.pdf

2. Usmani OS, Lavorini F, Marshall J, et al. Critical inhaler errors in asthma and COPD: a systematic review of impact on health outcomes. Respir Res. 2018;19:10. doi:10.1186/s12931-017-0710-y

3. Haidl P, Heindl S, Siemon K, et al. Inhalation device requirements for patients’ inhalation maneuvers. Respir Med. 2016;118:65-75. doi: 10.1016/j.rmed.2016.07.013

4. van Geffen WH, Douma WR, Slebos DJ, et al. Bronchodilators delivered by nebuliser versus pMDI with spacer or DPI for exacerbations of COPD. Cochrane Database Syst Rev. 2016;2016:CD011826. doi:10.1002/14651858.CD011826.pub2

5. Ghosh S, Ohar JA, Drummond MB. Peak inspiratory flow rate in chronic obstructive pulmonary disease: implications for dry powder inhalers. J Aerosol Med Pulm Drug Deliv. 2017;30:381-387. doi:10.1089/jamp.2017.1416

6. Iwanaga T, Tohda Y, Nakamura S, et al. The Respimat soft mist inhaler: implications of drug delivery characteristics for patients. Clin Drug Investig. 2019;39:1021-1030. doi:10.1007/s40261-019-00835-z

7. Navaie M, Dembek C, Cho-Reyes S, et al. Device use errors with soft mist inhalers: a global systematic literature review and meta-analysis. Chron Respir Dis. 2020;17:1479973119901234. doi:10.1177/1479973119901234

8. Sharma G, Mahler DA, Mayorga VM, et al. Prevalence of low peak inspiratory flow rate at discharge in patients hospitalized for COPD exacerbation. Chronic Obstr Pulm Dis. 2017;4:217-224. doi: 10.15326/jcopdf.4.3.2017.0183

9. Chen SY, Huang CK, Peng HC, et al. Peak-inspiratory-flow-rate guided inhalation therapy reduce severe exacerbation of COPD. Front Pharmacol. 2021;12:704316. doi: 10.3389/fphar.2021.704316

10. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains common in real life and is associated with reduced disease control. Respir Med. 2011;105:930-938. doi:10.1016/j.rmed.2011.01.005

11. Fathima M, Bawa Z, Mitchell B, et al. COPD management in community pharmacy results in improved inhaler use, immunization rate, COPD action plan ownership, COPD knowledge, and reductions in exacerbation rates. Int J Chron Obstruct Pulmon Dis. 2021;16:519-533. doi: 10.2147/COPD.S288792

12. van der Molen T, van Boven JF, Maguire T, et al. Optimizing identification and management of COPD patients – reviewing the role of the community pharmacist. Br J Clin Pharmacol. 2017;83:192-201. doi: 10.1111/bcp.13087

13. Brunetti L, Poiani G, Dhanaliwala F, et al. Clinical outcomes and treatment cost comparison of levalbuterol versus albuterol in hospitalized adults with chronic obstructive pulmonary disease or asthma. Am J Health Syst Pharm. 2015;72:1026-1035. doi:10.2146/ajhp140551

14. Brown CD, McCrory DC, White J. Inhaled short-acting beta2-agonists versus ipratropium for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2001;2001:CD002984. doi: 10.1002/14651858.CD002984

15. Kew KM, Mavergames C, Walters JAE. Long-acting beta₂-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013;(10):CD010177. doi: 10.1002/14651858.CD010177.pub2

16. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014;2014:CD009285. doi:10.1002/14651858.CD009285.pub3

17. Chong J, Karner C, Poole P. Tiotropium versus long-acting beta-agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;2012:CD009157. doi:10.1002/14651858.CD009157.pub2

18. Nannini LJ, Lasserson TJ, Poole P. Combined corticosteroid and long-acting beta₂-agonist in one inhaler versus long-acting beta₂-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;2012:CD006829. doi: 10.1002/14651858.CD006829.pub2

19. Yun JH, Lamb A, Chase R, et al; COPDGene and ECLIPSE Investigators. Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2018;141:2037-2047.e10. doi:10.1016/j.jaci.2018.04.010

20. Agusti A, Fabbri LM, Singh D, et al. Inhaled corticosteroids in COPD: friend or foe? Eur Respir J. 2018;52:1801219. doi:10.1183/13993003.01219-2018

21. Kew KM, Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2014:CD010115. doi: 10.1002/14651858.CD010115.pub2

22. Calverley PMA, Anderson JA, Celli B, et al; TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789. doi:10.1056/NEJMoa063070

23. Vestbo J, Anderson JA, Brook RD, et al; SUMMIT Investigators. Fluticasone furoate and vilanterol and survival in chronic obstructive pulmonary disease with heightened cardiovascular risk (SUMMIT): a double-blind randomised controlled trial. Lancet. 2016;387:1817-1826. doi:10.1016/S0140-6736(16)30069-1

24. Farne HA, Cates CJ. Long-acting beta₂-agonist in addition to tiotropium versus either tiotropium or long-acting beta₂-agonist alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2015:CD008989. doi:10.1002/14651858.CD008989.pub3

25. Horita N, Goto A, Shibata Y, et al. Long-acting muscarinic antagonist (LAMA) plus long-acting beta-agonist (LABA) versus LABA plus inhaled corticosteroid (ICS) for stable chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2017;2:CD012066. doi:10.1002/14651858.CD012066.pub2

26. Papi A, Vestbo J, Fabbri L, et al. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial. Lancet. 208;391:1076-1084. doi:10.1016/S0140-6736(18)30206-X

27. Vestbo J, Papi A, Corradi M, et al. Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial. Lancet. 2017;389:1919-1929. doi: 10.1016/S0140-6736(17)30188-5

28. Rabe KF, Martinez FJ, Ferguson GT, et al; ETHOS Investigators. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med. 2020;383:35-48. doi:10.1056/NEJMoa1916046

29. Rojas-Reyes MX, García Morales OM, Dennis RJ, et al. Combination inhaled steroid and long-acting beta₂-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 20162016:CD008532. doi: 10.1002/14651858.CD008532.pub3

30. Sonnex K, Alleemudder H, Knaggs R. Impact of smoking status on the efficacy of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review. BMJ Open. 2020;10:e037509. doi:10.1136/bmjopen-2020-037509

31. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med. 2002;166:675-679. doi:10.1164/rccm.2112096

32. Au DH, Bryson CL, Chien JW, et al. The effects of smoking cessation on the risk of chronic obstructive pulmonary disease exacerbations. J Gen Intern Med. 2009;24:457-463. doi:10.1007/s11606-009-0907-y

33. Anthonisen NR, Skeans MA, Wise RA, et al. The effects of a smoking cessation intervention on 14.5-year mortality: a randomized clinical trial. Ann Intern Med. 2005;142:233-239. doi: 10.7326/0003-4819-142-4-200502150-00005

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Author and Disclosure Information

Carl R. Darnall Army Medical Center, Uniformed Services University of the Health Sciences, Fort Hood, TX
scalpelandyardstick@gmail.com

The authors reported no potential conflict of interest relevant to this article.

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Army, Department of Defense, or the US Government.

Issue

The Journal of Family Practice - 71(7)

Publications

MDedge Family Medicine

The Journal of Family Practice

Topics

Pulmonology

Page Number

280-289

Sections

Applied Evidence

Author(s)

Michael Arnold, DO, FAAFP

Cate Vordtriede, PharmD, BCPS

Christina Chadwick, DO, MS, ARDMS

Evan Trivette, MD, MMAS

Author(s)

Michael Arnold, DO, FAAFP

Cate Vordtriede, PharmD, BCPS

Christina Chadwick, DO, MS, ARDMS

Evan Trivette, MD, MMAS

Author and Disclosure Information

Carl R. Darnall Army Medical Center, Uniformed Services University of the Health Sciences, Fort Hood, TX
scalpelandyardstick@gmail.com

The authors reported no potential conflict of interest relevant to this article.

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Army, Department of Defense, or the US Government.

Author and Disclosure Information

Carl R. Darnall Army Medical Center, Uniformed Services University of the Health Sciences, Fort Hood, TX
scalpelandyardstick@gmail.com

The authors reported no potential conflict of interest relevant to this article.

The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the US Army, Department of Defense, or the US Government.

Article PDF

JFP07109280.pdf

Article PDF

JFP07109280.pdf

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

Choose the right delivery device and drug while considering patient factors.
Provide patient education through allied health professionals.
Reduce environmental exposures.
Rethink the use of inhaled corticosteroids (ICS).
Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.²Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹

Last, keep in mind that evidence is limited regarding escalating the dosage of these agents (1) beyond what is listed in TABLE 2¹ and (2) in specific instances mentioned in the discussion of each inhaler class.

^awww.copdfoundation.org/Learn-More/EducationalMaterials-Resources/Educational-Video-Series.aspx

^bwww.thoracic.org/members/assemblies/assemblies/srn/questionaires/sgrq.php

^c Not an FDA-approved combination inhaled-agent treatment; approved in the European Union, under various brand names, by the European Medicines Agency.

CORRESPONDENCE
Michael Arnold, DO, FAAFP, Carl R. Darnall Army Medical Center, Uniformed Service University, 36065 Santa Fe Avenue, Fort Hood, TX 76544; scalpelandyardstick@gmail.com

Managing chronic obstructive pulmonary disease (COPD) presents a significant challenge to busy clinicians in many ways, especially when one is approaching the long list of inhaled pharmaceutical agents with an eye toward a cost-effective, patient-centered regimen. Inhaled agents remain expensive, with few available in generic form.

Our primary goal in this article is to detail these agents’ utility, limitations, and relative cost. Specifically, we review why the following considerations are important:

Choose the right delivery device and drug while considering patient factors.
Provide patient education through allied health professionals.
Reduce environmental exposures.
Rethink the use of inhaled corticosteroids (ICS).
Understand the role of dual therapy and triple therapy.

Guidelines recommend reassessing inhaler technique at every visit and when evaluating treatment response.

There are numerous other treatment modalities for COPD that are recommended in national and international practice guidelines, including vaccination, pulmonary rehabilitation, home visits, phosphodiesterase-4 inhibitors, oral glucocorticoids, supplemental oxygen, and ventilatory support.¹ Discussion of those modalities is beyond the scope of this review.

Pathophysiology and pharmacotherapy targets

COPD is characterized by persistent respiratory symptoms and airflow limitation, usually due to airway or alveolar abnormalities, or both, caused by environmental and host factors.²Sustained lung parenchymal irritation results from exposure to noxious fumes generated by tobacco, pollution, chemicals, and cleaning agents. Host factors include lung immaturity at birth; genetic mutations, such as alpha-1 antitrypsin deficiency and dysregulation of elastase; and increased reactivity of bronchial smooth muscles, similar to what is seen in asthma.¹

IMAGE: © JOE GORMAN

Improving ventilation with the intention of relieving dyspnea is the goal of inhaler pharmacotherapy; targets include muscarinic receptors and beta 2-adrenergic receptors that act on bronchial smooth muscle and the autonomic nervous system. Immune modulators, such as corticosteroids, help reduce inflammation around airways.¹ Recent pharmacotherapeutic developments include combinations of inhaled medications and expanding options for devices that deliver drugs.

Delivery devices: Options and optimizing their use

Three principal types of inhaler devices are available: pressurized metered-dose inhalers (MDIs), dry-powder inhalers (DPIs), and soft-mist inhalers (SMIs). These devices, and nebulizers, facilitate medication delivery into the lungs (TABLE 1^3-9).

Errors in using inhalers affect outcome. Correct inhaler technique is essential for optimal delivery of inhaled medications. Errors in technique when using an inhaled delivery device lead to inadequate drug delivery and are associated with poor outcomes: 90% of patients make errors that are classified as critical (ie, those that reduce drug delivery) or noncritical.² Critical inhaler errors increase the risk of hospitalization and emergency department visits, and can necessitate a course of oral corticosteroids.¹⁰ Many critical errors are device specific; several such errors are described in TABLE 1.^3-9

Continue to: Patient education

Patient education is necessary to ensure that drug is delivered to the patient consistently, with the same expectation of effect seen in efficacy studies (which usually provide rigorous inhaler technique training and require demonstration of proficiency).^1,2,10 For the busy clinician, a multidisciplinary approach, discussed shortly, can help. Guidelines developed by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommend that inhaler technique be reassessed at every visit and when evaluating treatment response.¹TABLE 1^3-9 provides information on each device type, patient requirements for use, proper technique, common errors in use, and tips for optimizing delivery.

Inhaler education and assessment of technique that is provided to patients in collaboration with a clinical pharmacist, nursing staff, and a respiratory therapist can help alleviate the pressure on a time-constrained primary care physician. Furthermore, pharmacist involvement in the COPD management team meaningfully improves inhaler technique and medication adherence.^6,7 Intervention by a pharmacist correlates with a significant reduction in number of exacerbations; an increased likelihood that the patient has a COPD care plan and has received the pneumococcal vaccine; and an improvement in the mean health-related quality of life.^11,12

In primary care practices that lack robust multidisciplinary resources, we recommend utilizing virtual resources, such as educational videos, to allow face-to-face or virtual education. A free source of such resources is the COPD Foundation,^a a not-for-profit organization funded partly by industry.

Short- and long-acting inhaled medications for COPD

Each class of inhaled medication for treating COPD is discussed broadly in the following sections. TABLE 2¹ provides details about individual drugs, devices available to deliver them, and starting dosages.

Short-acting agents

These drugs are available in MDI, SMI, and nebulizer delivery devices. When portability and equipment burden are important to the patient, we recommend an MDI over a nebulizer; an MDI is as efficacious as a nebulizer in improving forced expiratory volume in 1 second (FEV₁) and reducing the length of hospital stay for exacerbations.⁴

Continue to: SABAs

Short-acting beta 2-adrenergic agonists (or beta-agonists [SABAs]). Beta-agonists are typically used to treat exacerbations. They facilitate bronchodilation by upregulating cyclic adenosine monophosphate, preventing smooth-muscle contraction, and reducing dynamic hyperinflation. The effect of a SABA lasts 4 to 6 hours.

In general, SABAs are not recommended for daily use in stable COPD. However, they can be useful, and appropriate, for treating occasional dyspnea and can confer additional symptom improvement when used occasionally along with a long-acting beta 2-adrenergic agonist (or beta-agonist [LABA]; discussed later).¹

Continue use of a long-acting bronchodilator during exacerbations, when feasible.

Albuterol, a commonly used SABA, is less expensive than, and just as effective as, same-class levalbuterol for decreasing breathlessness associated with acute exacerbations. There is no significant difference between the 2 drugs in regard to the incidence of tachycardia or palpitations in patients with cardiovascular disease.¹³

Although no significant differences have been observed in outcomes when a nebulizer or an MDI is used to administer a SABA, it’s wise to avoid continuous SABA nebulizer therapy, due to the increased risk of disease transmission through the generation of droplets.^1,4 Instead, it’s appropriate to use an MDI regimen of 1 to 3 puffs every hour for 2 to 3 hours, followed by 1 to 3 puffs every 2 to 4 hours thereafter, based on the patient’s response.^1,4

Short-acting muscarinic antagonists (SAMAs). Muscarinic antagonists achieve bronchodilation by blocking acetylcholine on muscarinic receptors. We do not specifically recommend SAMAs over SABAs for treating COPD exacerbations in our patients: There is no difference in improvement in FEV₁ during an acute exacerbation. Nebulized delivery of a SAMA raises concern for an increase in the risk of acute narrow-angle glaucoma, a risk that can be reduced by using a mask during administration.^1,14

Continue to: SABA + SAMA

SABA + SAMA. One combination formulation of the 2 short-term classes of drugs (albuterol [SABA] + ipratropium [SAMA]), US Food and Drug Administration (FDA)–approved for every-6-hour dosing, is available for SMI delivery devices and nebulizers. In the setting of a hospitalized patient who requires more frequent bronchodilator dosing, we use albuterol and ipratropium delivered separately (ie, dosed independently), with ipratropium dosed no more frequently than every 4 hours.

Long-acting agents

The mechanisms of long-acting agents are similar to those of their short-acting counterparts. The recommendation is to continue use of a long-acting bronchodilator during exacerbations, when feasible.¹

LABA monotherapy reduces exacerbations that result in hospitalization (number needed to treat [NNT] = 39, to prevent 1 hospitalization in an 8-month period).¹⁵ Specifically, formoterol at higher dosages reduces exacerbations requiring hospitalization (NNT = 23, to prevent 1 exacerbation in a 6-month to 3-year period).¹⁵ Evidence supports better control of symptoms when a LABA is combined with a long-acting muscarinic antagonist (LAMA; discussed shortly).^1,15

Adverse effects of LABAs include sinus tachycardia, tachyphylaxis, somatic tremors, and, less commonly, hypokalemia—the latter specific to the LABA dosage and concomitant use of a thiazide diuretic. Other adverse effects include a mild decrease in the partial pressure of O₂ and, in patients with heart failure, increased oxygen consumption. Although higher dosages are not associated with an increased incidence of nonfatal adverse events, there appears to be no additional benefit to higher dosages in regard to mortality, particularly in patients with stable COPD.^1,15

LAMA. Monotherapy with a LAMA reduces the severity of COPD symptoms and reduces the risk of exacerbations and hospitalization (NNT = 58, to prevent 1 hospitalization in a 3 to 48–month period).¹⁶ Tiotropium is superior to LABA as monotherapy in (1) reducing exacerbations (NNT = 33, to prevent 1 exacerbation in a 3 to 12–month period) and (2) being associated with a lower rate of all adverse events.¹⁷ LAMAs also confer additional benefit when used in combination with agents of other classes, which we discuss in a bit.

Continue to: The most commonly...

The most commonly reported adverse effect of a LAMA is dry mouth. Some patients report developing a bitter metallic taste in the mouth.¹

ICSs are not recommended as monotherapy in COPD.¹ However, an ICS can be combined with a LABA to reduce the risk of exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ However, this combination increases the risk of pneumonia in this population (number needed to harm [NNH] = 36, to cause 1 case of nonfatal pneumonia per year).¹⁸

ICSs increase the incidence of oropharyngeal candidiasis and hoarseness. In addition, ICSs increase the risk of pneumonia in some patients with COPD¹⁸—in particular, current smokers, patients ≥ 55 years of age, and patients with a history of pneumonia or exacerbations, a body mass index < 25, or severe COPD symptoms.^1,18 ICS therapy does reduce the risk of COPD exacerbations in patients with a history of asthma or with eosinophilia > 300 cells/μL and in those who have a history of hospitalization for COPD exacerbations.^19,20

When portability and equipment burden are important to the patient, consider a metereddose inhaler (MDI) over a nebulizer: An MDI is equally efficacious.

The risk of pneumonia is not equal across all ICS agents. Fluticasone increases the risk of pneumonia (NNH = 23, to cause 1 case of pneumonia in a 22-month period).²¹ Budesonide showed no statistically significant increase in risk of pneumonia.²² However, further studies on the risk of pneumonia with budesonide are needed because those cited in the Cochrane review²¹ were much smaller trials, compared to trials of fluticasone, and of low-to-moderate quality. Furthermore, evidence is mixed whether ICS monotherapy in COPD worsens mortality during an 18-month study period.^21-23

For these reasons, it’s reasonable to (1) exercise caution when considering the addition of an ICS to LABA therapy and (2) limit such a combination to the setting of severe disease (as discussed already).

Continue to: LABA + LAMA

LABA + LAMA. In a trial of patients with moderate-to-severe COPD, combining a LABA and a LAMA did not reduce the risk of exacerbations or hospitalizations, compared to LABA or LAMA monotherapy, but did improve subjects’ reported daily symptoms and quality of life scores (using the St. George’s Respiratory Questionnaire^b; NNT = 14 [LAMA monotherapy] and NNT = 9 [LABA monotherapy], both in a 3 to 12–month period).²⁴ However, another study that looked at patients with moderate-to-severe COPD found that combining a LABA and a LAMA led to fewer exacerbations (NNT = 22, to prevent 1 exacerbation in a 3 to 12–month period) and a lower risk of pneumonia (NNT = 93, to prevent 1 case of pneumonia in a 3 to 12–month period) than LABA + ICS.²⁵

LABA + ICS. This dual therapy is falling out of favor, compared to treatment with LABA + LAMA, because LABA + ICS formulations are less effective at reducing exacerbations and increase the risk of pneumonia in patients with moderate-to-severe COPD.^1,25 However, LABA + ICS therapy still has a role in a subset of patients with COPD (discussed in the section on ICS). A LABA combined with an ICS does reduce exacerbations in patients with severe COPD (NNT = 22, to prevent 1 exacerbation per year).¹⁸ Expect that the reported rates of candidiasis, hoarseness, and pneumonia associated with an ICS will be similar with LABA + ICS.¹⁸

LABA + LAMA + ICS. These are the newest combination inhaled agents approved for clinical use. It is recommended that escalation to such triple therapy be reserved for patients with persistent dyspnea on LAMA + LABA therapy and who have the factors (previously described) that suggest benefit from adding an ICS.¹ Several clinical trials have provided guidance:

In the 2018 TRIBUTE trial,²⁶ beclometasone (ICS) + formoterol (LABA) + glycopyrronium (LAMA) ^c outperformed indacaterol (LABA) + glycopyrronium for preventing moderate-to-severe exacerbations (NNT = 11, to prevent 1 exacerbation per year) in patients with symptomatic COPD who have severe or very severe airflow resistance and a history of a moderate-to-severe exacerbation during the previous year.
In the 2017 TRINITY trial,²⁷ beclometasone + formoterol + glycopyrronium^c outperformed tiotropium (LAMA) in preventing moderate-to-severe exacerbations (NNT = 9, to prevent 1 exacerbation per year) in patients with an FEV₁ < 50% and a history of ≥ 1 moderate-to-severe exacerbation during the previous year.
In the 2020 ETHOS trial,²⁸ budesonide + formoterol + glycopyrronium (approved by the FDA in 2020 under the brand name Breztri) outperformed both glycopyrrolate + formoterol (LABA) and budesonide (ICS) + formoterol in preventing moderate-to-severe exacerbations (NNT = 56 and 34, respectively, to prevent 1 exacerbation per year) in patients with moderate-to-severe COPD who had a history of ≥ 1 exacerbation in the previous year. Additionally, higher-dose budesonide + formoterol + glycopyrronium reduced 1-year mortality to a modest degree compared to glycopyrrolate + formoterol (NNT = 100, to prevent 1 death in a 12-month period).
A 2016 Cochrane review that compared tiotropium + LABA + ICS to tiotropium monotherapy²⁹ showed improvement in FEV₁ and patient-reported symptoms and quality of life scores. However, the review showed no difference in exacerbations or hospitalizations over a 1-year period.

Mitigating environmental exposures that affect inhaler medication efficacy

Tobacco smoke. Emphasizing smoking cessation is highly relevant in patients who are still smoking. Smoking impedes the efficacy of ICSs in reducing exacerbations of COPD.³⁰ Along with improved lung function, former smokers with COPD experience fewer exacerbations (NNT = 73, to prevent 1 exacerbation in a 4-year period for all former smokers; NNT = 33, to do so for smokers who quit > 10 years ago).^31,32

The continuous use of shortacting betaagonist nebulizer therapy can increase the risk of disease transmission through the generation of droplets.

A 2005 Veterans Health Administration study showed reduced mortality in smokers who were enrolled in a 10-week smoking cessation program, had access to nicotine replacement therapy, and received strong physician messaging.³³ Despite a 20% to 25% quit rate, the NNT was 56 to prevent 1 death in 14.5 years across the entire group. It is worth having patients take advantage of this 3-pronged approach if it is available in your community or health system.

Continue to: Exposure to air pollution

Exposure to air pollution. Air pollutants other than tobacco smoke remain important modifiable factors that impact COPD. These include organic and inorganic dusts, chemical agents and fumes, and burning of solid biomass (eg, wood, coal) indoors in open fires or poorly functioning stoves.¹ With this risk in mind, counsel patients regarding efficient home ventilation, use of nonpolluting cooking stoves, and the reduction of occupational exposure to these potential irritants.

GOLD approach to starting and adjusting inhaled therapy

Initiating inhaled therapy

A good resource for family physicians is the GOLD refined ABCD assessment scheme for initiating inhaler therapy that integrates symptoms and exacerbations (TABLE 3¹). To assess the severity of dyspnea, either the Modified Medical Research Council (mMRC) Questionnaire or COPD Assessment Test (CAT) can be used. A moderate exacerbation requires an oral corticosteroid or antibiotic, or both; a severe exacerbation requires an emergency department visit or hospitalization, or both. TABLE 3¹ offers a guide to choosing initial therapy based on these factors.¹

Following up on and adjusting an inhaler regimen

Adjust inhaler pharmacotherapy based on whether exacerbations or daily symptoms of dyspnea are more bothersome to the patient. Escalation of therapy involves adding other long-acting agents and is warranted for patients with exacerbations or severe or worsening dyspnea. Before escalating therapy with additional agents, reassess the appropriateness of the delivery device that the patient has been using and assess their adherence to the prescribed regimen.¹

Dyspnea predominates. Escalate with LABA + LAMA. For a patient already taking an ICS, consider removing that ICS if the original indication was inappropriate, no response to treatment has been noted, or pneumonia develops.¹

Exacerbations predominate. Escalate with LABA + LAMA or with LABA + ICS. Consider adding an ICS in patients who have a history of asthma, eosinophilia > 300 cells/uL, or eosinophilia > 100 cells/uL and 2 moderate exacerbations or 1 severe (ie, hospitalizing) exacerbation. This addition of an ICS results in dual or triple therapy (ie, either LABA + ICS or LABA + LAMA + ICS).¹

Continue to: Unclear what predominates?

Unclear what predominates? Follow the exacerbation predominance pathway.¹

Additional decision-making might be necessary in several circumstances:

For the patient who requires further titration beyond these pathways, consider triple therapy as LABA + LAMA + ICS, unless the eosinophil count is < 100 cell/μL.¹
Consider de-escalating ICS therapy if the patient develops pneumonia, there is a lack of demonstrated benefit, or the initial indication was uncertain or inappropriate.
For the patient who continues to have significant dyspnea despite dual or triple therapy, consider investigating and treating other causes of dyspnea.¹