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COPD optimizing treatment.

A guideline update and an expanded armamentarium have many physicians wondering how best to treat patients with COPD. Here's help.

Chronic obstructive pulmonary disease (COPD) carries a high disease burden. In 2012, it was the 4th leading cause of death worldwide. (1,2) In 2015, the World Health Organization updated its Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, classifying patients with COPD based on disease burden as determined by symptoms, airflow obstruction, and exacerbation history. (3) These revisions, coupled with expanded therapeutic options within established classes of medications and new combination drugs to treat COPD (TABLE 1), (3-6) have led to questions about interclass differences and the best treatment regimen for particular patients.

Comparisons of various agents within a therapeutic class and their impact on lung function and rate of exacerbations address many of these concerns. In the text and tables that follow, we present the latest evidence highlighting differences in dosing, safety, and efficacy. We also include the updated GOLD classifications, evidence of efficacy for pulmonary rehabilitation, and practical implications of these findings for the optimal management of patients with COPD.

But first, a word about terminology.

Understanding COPD

COPD is a chronic lung disease characterized by progressive airflow limitation, usually measured by spirometry (table 2), (3) and chronic airway inflammation. Emphysema and chronic bronchitis are often used synonymously with COPD. In fact, there are important differences.

Individuals with chronic bronchitis do not necessarily have the airflow limitations found in those with COPD. And patients with COPD develop pathologic lung changes beyond the alveolar damage characteristic of emphysema, including airway fibrosis and inflammation, luminal plugging, and loss of elastic recoil. (3)

The medications included in this review aim to reduce both the morbidity and mortality associated with COPD. These drugs can also help relieve the symptoms of patients with chronic bronchitis and emphysema, but have limited effect on patient mortality.

Short- and long-acting [beta.sub.2]-agonists

Bronchodilator therapy with [beta.sub.2]-agonists improves forced expiratory volume in one second ([FEV.sub.1]) through relaxation of airway smooth muscle. [beta.sub.2]-agonists have proven to be safe and effective when used as needed or scheduled for patients with COPD. (7)

Inhaled short-acting [beta.sub.2]-agonists (SABAs) improve [FEV.sub.1] and symptoms within 10 minutes, with effects lasting up to 4 to 6 hours; long-acting [beta.sub.2]-agonists (LABAs) have a variable onset, with effects lasting 12 to 24 hours. (8) Inhaled levalbuterol, the last SABA to receive US Food and Drug Administration approval, has not proven to be superior to conventional bronchodilators in ambulatory patients with stable COPD. (3) In clinical trials, however, the slightly longer half-life of the nebulized formulation of levalbuterol was found to reduce both the frequency of administration and the overall cost of therapy in patients hospitalized with acute exacerbations of COPD. (9,10)

Recently approved LABAs

Clinical trials have studied the safety and efficacy of newer agents vs older LABAs in patients with moderate to severe COPD. Compared with theophylline, for example, formoterol 12 meg inhaled every 12 hours for a 12-month period provided a clinically significant increase of >120 ml in [FEV.sub.1] (P=.026). (11) Higher doses of formoterol did not provide any additional improvement.

In a trial comparing indacaterol and tiotropium, an inhaled anticholinergic, both treatment groups had a clinically significant increase in [FEV.sub.1], but patients receiving indacaterol achieved an additional increase of 40 to 50 mL at 12 weeks. (12)

Exacerbation rates for all LABAs range from 22% to 44%. (5,12,13) In a study of patients receiving formoterol 12 meg compared with 15-mcg and 25-mcg doses of arformoterol, those taking formoterol had a lower exacerbation rate than those on either strength of arformoterol (22% vs 32% and 31%, respectively). (10) In various studies, doses greater than the FDA-approved regimens for indacaterol, arformoterol, and olodaterol did not result in a significant improvement in either [FEV.sub.1] or exacerbation rates compared with placebo. (5,12,14)

Studies that assessed the use of rescue medication as well as exacerbation rates in patients taking LABAs reported reductions in the use of the rescue drugs ranging from 0.46 to 1.32 actuations per day, but the findings had limited clinical relevance. (5,13) With the exception of indacaterol and olodaterol--both of which may be preferable because of their once-daily dosing regimen--no significant differences in safety and efficacy among LABAs have been found. (5,12,13)

Long-acting inhaled anticholinergics

Inhaled anticholinergic agents (IACs) can be used in place of, or in conjunction with, LABAs to provide bronchodilation for up to 24 hours. (3) The introduction of long-acting IACs dosed once or twice daily has the potential to improve medication adherence over traditional short-acting ipratropium, which requires multiple daily doses for symptom control. Over 4 years, tiotropium has been shown to increase time to first exacerbation by approximately 4 months. It did not, how ever, significantly reduce the number of exacerbations compared with placebo. (15)

Long-term use of tiotropium appears to have the potential to preserve lung function. In one trial, it slowed the rate of decline in [FEV.sub.1] by 5 mL per year, but this finding lacked clinical significance. (13) In clinical trials of patients with moderate to severe COPD, however, once-daily tiotropium and umeclidinium provided clinically significant improvements in [FEV.sub.1] (>120 mL; P<.01), regardless of the dose administered. (6,16) In another trial, patients taking aclidinium 200 meg or 400 meg every 12 hours did not achieve a clinically significant improvement in [FEV.sub.1] compared with placebo. (17)

In patients with moderate to severe COPD, the combination of umeclidinium/ vilanterol, a LABA, administered once daily resulted in a clinically significant improvement in [FEV.sub.1] (167 mL; P<.001) vs placebo--but was not significantly better than treatment with either agent alone. (18)

Few studies have evaluated time to exacerbation in patients receiving aclidinium or umeclidinium. In comparison to salmeterol, tiotropium reduced the time to first exacerbation by 42 days at one year (hazard ratio=0.83; 95% confidence interval [CI], 0.77-0.9; P<.001). (19) The evidence suggests that when used in combination with LABAs, long-acting IACs have a positive impact on [FEV.sub.1], but their effect on exacerbation rates has not been established.

Combination therapy with steroids and LABAs

The combination of inhaled corticosteroids (ICS) and LABAs has been found to improve [FEV.sub.1] and symptoms in patients with moderate to severe COPD more than monotherapy with either drug class. (20,21) In fact, ICS alone have not been proven to slow the progression of the disease or to lower mortality rates in patients with COPD. (22)

Fluticasone/salmeterol demonstrated a 25% reduction in exacerbation rates compared with placebo (P<.0001), a greater reduction than that of either drug alone. (20) A retrospective observational study comparing fixed dose fluticasone/salmeterol with budesonide/formoterol reported a similar reduction in exacerbation rates, but the number of patients requiring the addition of an IAC was 16% lower in the latter group. (23)

The combination of fluticasone/vilanterol has the potential to improve adherence, given that it is dosed once daily, unlike other COPD combination drugs. Its clinical efficacy is comparable to that of fluticasone/salmeterol after 12 weeks of therapy, with similar improvements in [FEV.sub.1], (24) but fluticasone/ vilanterol is associated with an increased risk of pneumonia. (3)

Chronic use of oral corticosteroids

Oral corticosteroids (OCS) are clinically indicated in individuals whose symptoms continue despite optimal therapy with inhaled agents that have demonstrated efficacy. Such patients are often referred to as "steroid dependent."

While OCS are prescribed for both their anti-inflammatory activity and their ability to slow the progression of COPD, (25,26) no well-designed studies have investigated their benefits for this patient population. One study concluded that patients who were slowly withdrawn from their OCS regimen had no more frequent exacerbations than those who maintained chronic usage. The withdrawal group did, however, lose weight. (27)

GOLD guidelines do not recommend OCS for chronic management of COPD due to the risk of toxicity. (3) The well-established adverse effects of chronic OCS include hyperglycemia, hypertension, osteoporosis, and myopathy. (28,29) A study of muscle function in 21 COPD patients receiving corticosteroids revealed decreases in quadriceps muscle strength and pulmonary function. (30) Daily use of OCS will likely result in additional therapies to control drug-induced conditions, as well--another antihypertensive secondary to fluid retention caused by chronic use of OCS in patients with high blood pressure, for example, or additional medication to control elevated blood glucose levels in patients with diabetes.

Phosphodiesterase-4 inhibitors

The recommendation for roflumilast in patients with GOLD Class 2 to 4 symptoms remains unchanged since the introduction of this agent as a treatment option for COPD. (3) Phosphodiesterase-4 (PDE-4) inhibitors such as roflumilast reduce inflammation in the lungs and have no activity as a bronchodilator. (31,32)

Roflumilast has been shown to improve [FEV.sub.1] in patients concurrently receiving a long-acting bronchodilator and to reduce exacerbations in steroid-dependent patients, a recent systematic review of 29 PDE-4 trials found. (33) Patients taking roflumilast, however, suffered from more adverse events (nausea, appetite reduction, diarrhea, weight loss, sleep disturbances, and headache) than those on placebo. (33)


GOLD guidelines do not recommend the use of antibiotics for patients with COPD, except to treat acute exacerbations. (1) However, recent studies suggest that routine or pulsed dosing of prophylactic antibiotics can reduce the number of exacerbations. (34,36) A 2013 review of 7 studies determined that continuous antibiotics, particularly macrolides, reduced the number of COPD exacerbations in patients with a mean age of 66 years (odds ratio [OR]=0.55; 95% CI, 0.39-0.77). (37)

A more recent trial randomized 92 patients with a history of [greater than or equal to] 3 exacerbations in the previous year to receive either prophylactic azithromycin or placebo daily for 12 months. The treatment group experienced a significant decrease in the number of exacerbations (OR=0.58; 95% CI, 0.42-0.79; P=001). (38) This benefit must be weighed against the potential development of antibiotic resistance and adverse effects, so careful patient selection is important.

Pulmonary rehabilitation has proven benefits

GOLD, the American College of Chest Physicians, the American Thoracic Society, and the European Respiratory Society all recommend pulmonary rehabilitation for patients with COPD. (39,41) In addition to reducing morbidity and mortality rates--including a reduction in number of hospitalizations and length of stay and improved post-discharge recovery--pulmonary rehabilitation has been shown to have other physical and psychological benefits. (42) Specific benefits include improved exercise capacity, greater arm strength and endurance, reduced perception of intensity of breathlessness, and improved overall health-related quality of life.

Key features of rehab programs

Important components of pulmonary rehabilitation include counseling on tobacco cessation, nutrition, education--including correct inhalation technique--and exercise training. There are few contraindications to participation, and patients can derive benefit from both its non-exercise components and upper extremity training regardless of their mobility level.

A 2006 Cochrane review concluded that an effective pulmonary rehabilitation program should be at least 4 weeks in duration, (43) and longer programs have been shown to produce greater benefits. (44) However, there is no agreement on an optimal time frame. Studies are inconclusive on other specific aspects of pulmonary rehab programs, as well, such as the number of sessions per week, number of hours per session, duration and intensity of exercise regimens, and staff-to-patient ratios.

* Home-based exercise training may produce many of the same benefits as a formal pulmonary rehabilitation program. A systematic review found improved quality of life and exercise capacity associated with patient care that lacked formal pulmonary rehabilitation, with no differences between results from home-based training and hospital-based outpatient pulmonary rehabilitation programs. (45)

Given the lack of availability of formal rehab programs in many communities, home-based training for patients with COPD is important to consider.

Implications for practice

What is the takeaway from this evidence-based review? Overall, it is clear that, with the possible exception of the effect of once-daily dosing on adherence, there is little difference among the therapeutic agents within a particular class of medications--and that more is not necessarily better. Indeed, evidence suggests that higher doses of LABAs may reduce their effectiveness, rendering them no better than placebo. In addition, there is no significant difference in the rate of exacerbations in patients taking ICS/LABA combinations and those receiving IACs alone.

Pulmonary rehabilitation should be recommended for all newly diagnosed patients, while appropriate drug therapies should be individualized based on the GOLD symptoms/risk evaluation categories (table 3). (3) While daily OCS and daily antibiotics have the potential to reduce exacerbation rates, for example, the risks of adverse effects and toxicities outweigh the benefits for patients whose condition is stable.

Determining the optimal treatment for a particular patient also requires an assessment of comorbidities, including potential adverse drug effects (table 4). (3,27-29,33,46-52) Selection of medication should be driven by patient and physician preference to optimize adherence and clinical outcomes, although cost and accessibility often play a significant role, as well.


* Individualize treatment regimens based on severity of symptoms and risk for exacerbation, prescribing short-acting [beta.sub.2]-agonists, as needed, for all patients with chronic obstructive pulmonary disease (COPD). (A)

* Limit use of inhaled long-acting [beta.sub.2]-agonists to the recommended dosage; higher doses do not lead to better outcomes. (A)

Strength of recommendation (SOR)

(A) Good-quality patient-oriented evidence

(B) Inconsistent or limited-quality patient-oriented evidence

(C) Consensus, usual practice, opinion, disease-oriented evidence, case series

Nabila Ahmed-Sarwar, PharmD, BCPS, CDE; Deirdre P. Pierce, PharmD, BCPS, CGP; David C. Holub, MD, FAAFP

St. John Fisher College, Wegmans School of Pharmacy, Rochester,

NY (Drs. Ahmed-Sarwar and Pierce); University of Rochester Family Medicine Residency Program (Drs. Ahmed-Sarwar and Holub)


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


Nabila Ahmed-Sarwar, PharmD, BCPS, CDE, St. John Fisher College, Wegmans School of Pharmacy, 3690 East Avenue, Rochester, NY 14618;


The authors thank the following people for their assistance in the preparation of this manuscript: Matthew Stryker, PharmD, Timothy Adler, PharmD, and Angela K. Nagel, PharmD, BCPS.


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(24.) Dransfield MT, Feldman G, Korenblat P, et al. Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 meg) versus twice-daily fluticasone propionate/salmeterol (250/50 meg) in COPD patients. Respir Med. 2014;108:1171-1179.

(25.) Davies L, Nisar M, Pearson MG, et al. Oral corticosteroid trials in the management of stable chronic obstructive pulmonary disease. QJM. 1999;92:395-400.

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(28.) Clore JN, Thurby-Hay L. Glucocorticoid-induced hyperglycemia. EndocrPract. 2009;15:469-474.

(29.) McEvoy CE, Ensrud KE, Bender E, et al. Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:704-709.

(30.) Decramer M, Lacquet LM, Fagard R, et al. Corticosteroids contribute to muscle weakness in chronic airflow obstruction. Am J Respir Crit Care Med. 1994; 150:11-16.

(31.) Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al; M2-127 and M2-128 study groups. Roflumilast in moderate-to-severe chronic obstructive pulmonary disease treated with longacting bronchodilators: two randomised clinical trials. Lancet. 2009;374:695-703.

(32.) Calverley PM, Rabe KF, Goehring UM, et al; M2-124 and M2-125 study groups. Roflumilast in symptomatic chronic obstructive pulmonary disease: two randomised clinical trials. Lancet. 2009;374:685-694.

(33.) Chong J, Leung B, Poole P. Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2013; 11: C D002309.

(34.) Seemungal TA, Wilkinson TM, Hurst JR, et al. Long-term erythromycin therapy is associated with decreased chronic obstructive pulmonary disease exacerbations. Am J Respir Crit Care Med. 2008;178:1139-1147.

(35.) Sethi S, Jones PW, Rieron MS, et al; PULSE study group. Pulsed moxifloxacin for the prevention of exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial. Respir Res. 2010;11:10.

(36.) Albert RK, Connett J, Bailey WC, et al; COPD Clinical Research Network. Azithromycin for prevention of exacerbations of COPD. N Engl J Med. 2011;365:689-698.

(37.) Herath SC, Poole P. Prophylactic antibiotic therapy for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2013;11:CD009764.

(38.) Uzun S, Djamin RS, Kluytmans JA, et al. Azithromycin maintenance treatment in patients with frequent exacerbations of chronic obstructive pulmonary disease (COLUMBUS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2014;2:361-368.

(39.) Ries AL, Bauldoff GS, Carlin BW, et al. Pulmonary rehabilitation: joint ACCP/AACVPR evidence-based clinical practice guidelines. Chest. 2007;131:S4-S42.

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COPD: Assessing newer inhaled treatments (3-6)

Drug/dose (trade name)      Dosing      Evidence


Arformoterol                12          Evidence level not assessed
15 mcg/2 mL solution for                in current guidelines
nebulization (Brovana)
                                        Nebulized arformoterol MDI
                                        resulted in a clinically
                                        significant higher % change
                                        in FEV, vs salmeterol

                                        Slightly higher exacerbation
                                        rates with arformoterol than
                                        with formoterol

Indacaterol DPI 75 meg      24          Bronchodilator effect greater
(Arcapta Neohaler)                      than salmeterol and
                                        formoterol; similar to

                                        Decreases breathlessness and
                                        exacerbations, improves
                                        overall health status

Long-acting IACs

Aclidinium bromide          12          Evidence level not determined
400 meg DPI (Tudorza                    in current guidelines, but
Pressair)                               statement notes that
                                        aclidinium is similar to
                                        tiotropium for lung function
                                        and shortness of breath

Tiotropium                  24          Reduces exacerbations and
17 meg DPI (Spiriva                     hospitalizations, improves
Handihaler)                             symptoms and effectiveness of
                                        pulmonary rehabilitation

Umeclidinium bromide        24          Not assessed in current
62.5 meg DPI                            guidelines; active comparator
(Incruse Ellipta)                       trials pending

                                        Compared with placebo,
                                        umeclidinium resulted in
                                        clinically significant
                                        improvements in [FEV.sub.1]


ICS + LABA                  24          ICS + a LABA or long-acting
                                        IAC is more effective than
Fluticasone + vilanterol                individual components in
100/25 DPI                              improving lung function and
(Breo Ellipta)                          health status in patients
                                        with moderate to very severe

                                        Combination therapy is
                                        associated with an increased
                                        risk of pneumonia, but with
                                        no other significant adverse

LABA + IAC                  24          Not assessed in current
Umeclidinium + vilanterol
62.5/25 DPI                             Product improved lung
(Anoro Ellipta)                         function vs monotherapy with

COPD, chronic obstructive pulmonary disease; DPI, dry powder inhaler;
IAC, inhaled anticholinergic agent; ICS, inhaled corticosteroid;
LABA, long-acting [beta.sub.2]-agonist; MDI, metered dose inhaler

GOLD classification of severity of airflow limitations (3)

In patients with [FEV.sub.1]/FVC <0.70

Class 1   Mild          [FEV.sub.1] [greater than or equal to] 80%

Class 2   Moderate      [FEV.sub.1] [greater than or equal to] 50% to
                        <80% predicted

Class 3   Severe        [FEV.sub.1] [greater than or equal to] 30% to
                        <50% predicted

Class 4   Very severe   [FEV.sub.1] <30% predicted

[FEV.sub.1], forced expiratory volume in one second; FVC, forced
vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung

Recommended therapies based on GOLD classification (a)

Category            Characteristics             First-line therapies

A (Class 1 and 2)   Low risk, less symptoms     Pulmonary
                                                rehabilitation and
                                                short-acting IAC or

B (Class 1 and 2)   Low risk, more symptoms     Therapies for
                                                category A and
                                                long-acting IAC or

C (Class 3 and 4)   High risk, less symptoms    Therapies for
                                                category A and ICS +
                                                LABA or long-acting

D (Class 3 and 4)   High risk, more symptoms    Therapies for
                                                category A and ICS +
                                                LABA and/or
                                                long-acting IAC
                                                and/or PDE-4

GOLD, Global Initiative for Chronic Obstructive Lung Disease; IAC,
inhaled anticholinergic; ICS, inhaled corticosteroid; LABA,
long-acting [beta.sub.2]-agonist; PDE-4, phosphodiesterase-4; SABA,
short-acting [beta.sub.2]-agonist.

Adverse effects to consider in treatment selection

Medication class   Common adverse effects  Clinical impact

Inhaled            Tachycardia,            Adverse effects more
[beta.sub.2]-      dyspepsia, nausea,      pronounced with SABAs vs
agonists           nervousness,            LABAs (46,47)
                   tremor (46,47)          Inhaled anticholinergics
                                           may be an appropriate
                                           alternative to inhaled
                                           [beta.sub.2]-agonists for
                                           patients with a history of
                                           anxiety, arrhythmias,
                                           dilated cardiomyopathy,
                                           ischemic heart disease,
                                           insomnia, or gastric
                                           reflux (3)

                                           May be less effective in
                                           patients on non-selective
                                           beta-blockers (3)

Inhaled            Dry mouth (48)          Poor systemic absorption
anticholinergics                           following inhalation (48)

                                           May be preferable to
                                           inhaled [beta.sub.2]-
                                           agonists for elderly
                                           patients or those with
                                           multiple comorbidities due
                                           to safety profile (3,49)

                                           Combination of inhaled
                                           anticholinergics and
                                           smaller doses of
                                           provide improvements in
                                           [FEV.sub.1] with fewer
                                           systemic adverse
                                           effects (3)

Inhaled            Oral candidiasis        Immunocompromised patients
corticosteroids    and pneumonia (50)      and those with
                                           uncontrolled diabetes are
                                           at higher risk (50)

                                           Counseling on proper
                                           administration technique
                                           may prevent adverse

Continuous         GI distress (nausea,    Crohn's disease, IBS, and
antibiotics        vomiting,               other conditions affecting
                   diarrhea) (51)          GI motility may be
                                           exacerbated with chronic
                                           use of macrolide
                                           antibiotics (51)

                   Antibiotic              Development of antibiotic
                   resistance (51)         resistance limits choice
                                           of antimicrobials for
                                           acute infections

Oral               Hyperglycemia,          Well established
corticosteroids    hypertension,           relationship with multiple
(daily)            reduced bone mineral    chronic conditions that
                   density, and muscle     significantly impact
                   weakness (3,27-29)      morbidity and mortality (3)

                                           Daily oral corticosteroid
                                           use will likely result in
                                           additional therapies to
                                           control drug-induced
                                           conditions (3)

PDE-4 inhibitors   GI discomfort,          Most common adverse
                   headache, worsening     effects are transient (52)
                   depression, and
                   weight loss (33,52)     Depression is a common
                                           comorbid condition in
                                           patients with COPD.
                                           Pulmonary rehabilitation
                                           has been determined to
                                           improve symptoms of
                                           depression and should be
                                           considered along with
                                           pharmacotherapy for
                                           depression in patients
                                           receiving PDE-4
                                           inhibitors (3)

                                           PDE-4 inhibitor use is
                                           associated with weight
                                           loss; functional status
                                           and stability should be
                                           assessed frequently to
                                           reduce the risk of falls

COPD, chronic obstructive pulmonary disease; [FEV.sub.1], forced
expiratory volume in one second; GI, gastrointestinal; IBS, irritable
bowel syndrome; LABAs, long-acting [beta.sub.2]-agonists; PDE-4,
phosphodiesterase-4; SABAs, short-acting [beta.sub.2]-agonists.
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Article Details
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Title Annotation:chronic obstructive pulmonary disease
Author:Ahmed-Sarwar, Nabila; Pierce, Deirdre P.; Holub, David C.
Publication:Journal of Family Practice
Article Type:Cover story
Date:Oct 1, 2015
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