Treatment Options in Chronic Obstructive Pulmonary Disease: Current Recommendations and Recent Findings

ABSTRACT: Pharmacologic treatments and pulmonary rehabilitation improve symptoms, health status, and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD). Short-acting and long-acting bronchodilators are the mainstays of therapy for as-needed symptom relief and long-term maintenance, respectively. Disease severity, device characteristics, medication costs, and patient preferences are factors to consider when making pharmacologic treatment decisions. Changes in symptoms, adherence to treatment, and existence of comorbidities should be assessed when evaluating the effectiveness of pharmacologic therapy. Pulmonary rehabilitation, including exercise training, nutritional counseling, psychosocial support, and patient education, has shown clinical benefits at all COPD severity stages. Oxygen therapy and surgical options may be considered in carefully selected patients. Research is ongoing to develop novel therapies that can modify disease progression and to identify COPD phenotypes for greater individualization of therapy. This article reviews current COPD treatment recommendations and potential novel COPD treatment options for the future.
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Patients with chronic obstructive pulmonary disease (COPD) can exhibit a significant response to bronchodilator therapy^1-5; as such, short-acting and long-acting bronchodilator therapies are the mainstays of COPD treatment.⁶ Goals of pharmacotherapy and other elements of COPD management (eg, pulmonary rehabilitation, smoking cessation) are to relieve symptoms; prevent disease progression; improve exercise tolerance, health status, and quality of life; prevent and treat complications and exacerbations; and reduce mortality.⁶ Identification of comorbidities, which can complicate treatment and result in poor outcomes, also is necessary.⁶ COPD treatment is selected based on severity and
exacerbation frequency, clinical presentation, speed of lung function
decline, extrapulmonary effects, comorbidities, and patient factors.⁷

PHARMACOLOGIC TREATMENT OPTIONS

Table 1 summarizes available COPD medications.⁶ Regardless of other therapies, all COPD patients should have short-acting ß₂-adrenergic agonists (SABAs) and short-
acting anticholinergics available for rapid symptom relief.⁶ SABAs relax airway smooth muscles,⁶ while short-acting anticholinergics block the bronchoconstrictive effects of acetylcholine on airway smooth muscle cells.^6,8

Long-acting bronchodilators, including long-acting muscarinic antagonists (LAMAs) and long-acting ß₂-adrenergic agonists (LABAs), are the mainstays of therapy for long-term COPD symptom management.⁶ Despite concerns stemming from asthma studies,^9-11 the safety of LAMAs and LABAs has been shown in patients with COPD.^8,12-14 The Understanding Potential Long-term Impacts on Function With Tiotropium (UPLIFT) study and a subsequent meta-analysis of 19 studies with tiotropium, including UPLIFT, showed no evidence of an increased risk of cardiovascular events.^12,13 The safety of LABA monotherapy in COPD is well documented^8,14; LAMAs and LABAs can be administered alone or as combination therapy for bronchodilation and reduction of symptoms and exacerbations.^6,14

Regular inhaled corticosteroid (ICS) therapy may further reduce exacerbation frequency for patients with severe or very severe COPD and a history of frequent exacerbations.⁶ ICS treatment has not been proven to slow lung function decline in patients with COPD,^6,15-18 but Towards a Revolution in COPD Health (TORCH) post hoc data suggest a slowing of lung function decline that should be further evaluated.¹⁹ ICS use in persons with COPD has been shown to increase the risk of pneumonia, which may vary by ICS type,^6,20-23 and high-dose ICS therapy increases fracture risk.²⁰ No increased risk of pneumonia was seen with inhaled budesonide (up to 640 µg/d) compared with placebo or formoterol alone over 12 months.²⁴ Oral corticosteroids are not recommended for long-term therapy in patients with COPD.⁶ However, a 7- to 10-day burst of oral prednisone is a mainstay of COPD exacerbation therapy.⁶

HOW TO SELECT PHARMACOLOGIC THERAPY

Treatments should be selected based on the patient’s disease severity and COPD exacerbation frequency (Figure 1).⁶ The type of delivery device²⁵ (eg, pressurized metered-dose inhaler, dry powder inhaler, or nebulizer), the skills and ability of the individual patient,⁶ the cost of each treatment (commonly US$36 to $210 per month²⁶), and the patient’s financial status also should be considered. Patients with COPD routinely take 4 to 10 medications daily for various indications.^27,28 Use of multiple types of inhaler devices can lead to confusion and errors in medication use^29,30; therefore, it may be advantageous for physicians to keep the device consistent if possible.³⁰ When used correctly, the device does not affect treatment efficacy³¹; however, it is important to ensure proper inhaler technique. At each clinic visit, a clinical team member should recheck the patient’s inhaler technique to ensure correct inhaler use.⁶ Information about inhaler devices, inhalation technique, and recommendations for training can be found here: http://advanceweb.com/web/AstraZeneca/focus_on_copd_issue3_DevicesForAerosol/focus_on_copd_issue3.html.³²

CHANGING PHARMACOLOGIC THERAPY

Patients with COPD should be monitored carefully for treatment response and side effects,⁶ and therapy should be individualized.⁶ Over time, all patients will require additional treatments or an increase in dose as disease severity worsens.⁶ However, COPD progression may not be recognized by patients over time.³³ It is important for physicians to evaluate patients for signs and symptoms of disease worsening,³³ including decreased exercise tolerance (what can the patient not do now that he/she could do last year?), impaired quality of life (what does the patient want to be able to do?), increased breathlessness at rest or during exercise (how many stairs can the patient go up before having to stop?), increased sputum (tablespoon versus a shot glass versus a cup full in a day), low or reduced oxygen saturation (pulse oximetry testing), change in ability to perform activities of daily living independently, and increased wheeze.³⁴

Assessment tools may help disease evaluations by providing physicians with clear and validated questions to ask patients. The Modified Medical Research Council (MMRC) dyspnea scale³⁵ (http://copd.about.com/od/copdbasics/a/MMRCdyspneascale.htm) and the modified Borg scale^36,37 (http://www.yourlunghealth.org/testing/6min_walk/index.cfm) can be used to follow disease progression if used repeatedly over time. The 8-item COPD Assessment Test (CAT) can be used to measure overall COPD-related health status (Figure 2),³⁸ and the 14-item Exacerbations of Chronic Pulmonary Disease Tool-Patient-Reported Outcome (EXACT-PRO)^39,40 (http://www.exactproinitiative.com/default.php#) can be used to quantify the severity of a COPD exacerbation.³⁹

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IMPORTANCE OF PATIENT ADHERENCE TO COPD MANAGEMENT

COPD requires life-long medication therapy, and adherence to therapy is critical to achieving treatment goals. Poor adherence is common in patients with COPD, and adherence tends to decline over time.^41,42 Thus, efforts to improve treatment adherence are worthwhile. Data from the TORCH study showed that good adherence (> 80% of doses) to inhaled COPD medication is associated with a significantly decreased risk of mortality and hospital admission for severe exacerbations over 3 years.⁴³

Factors related to the patient (eg, health beliefs, self-efficacy, comorbidities, psychologic profile), the treatment (eg, dosing regimen, polypharmacy, side effects, method of administration), society (eg, social support, patient-prescriber relationship, access to medication, inhaler technique training), and health professionals (eg, education, goal setting, regular follow-up visits) can affect adherence.⁴¹ In particular, depression is a major contributor to poor adherence in patients with COPD, and its treatment substantially improves quality of life.⁴⁴ Questionnaires including the Hospital Anxiety and Depression Questionnaire⁴⁴ and the Patient Health Questionnaire-9⁴⁵ can help to identify patients who have significant anxiety and depression.

PULMONARY REHABILITATION

Pulmonary rehabilitation improves exercise capacity and health-related quality of life and reduces hospitalizations, perceived dyspnea intensity, anxiety, and depression in patients across all COPD severity levels.⁶ Components include exercise training, nutrition counseling, psychosocial support, and education.^6,46 Exercise training programs generally range from 4 to 10 weeks, with greater benefits observed with longer programs.^6,44 Strength training is especially important for patients with substantial muscle atrophy,⁴⁴ while inspiratory muscle training may improve inspiratory muscle strength and decrease dyspnea.⁴⁷ As part of nutrition counseling, physicians should ensure that patients with COPD who are underweight have adequate caloric intake and overweight patients have a diet that encourages fat loss.⁴⁶ Maintenance of pulmonary rehabilitation is important, as benefits wane without continued exercise.⁶

LONG-TERM OXYGEN THERAPY

Patients with very severe COPD may require oxygen therapy to ensure that vital organs receive adequate oxygen.⁶ Supplemental oxygen therapy improves exercise capacity, ventilation, and neuropsychological performance (ie, memory and learning).⁴⁸ The need for long-term oxygen therapy (> 15 hours per day), which increases survival in patients with chronic respiratory failure,⁶ is determined by the patient’s arterial blood gas values. Treatment goals include increased baseline partial pressure of arterial oxygen to ≥ 60 mm Hg and/or production of ≥ 90% oxygen saturation.⁶

SURGICAL TREATMENTS AND NEW AND EMERGING PHARMACOLOGIC TREATMENTS

Certain surgical treatments may be considered in carefully selected patients. Bullectomy, which involves removal of a large bulla in select patients with bullous emphysema, decompresses pulmonary parenchyma and improves pulmonary function and dyspnea.⁶ Lung volume reduction surgery improves expiratory flow rate by reducing hyperinflation and increasing lung elastic recoil.⁶ Compared with optimal medical therapy for severe COPD, lung volume reduction surgery has been shown to reduce the frequency of COPD exacerbations and increase the time to first exacerbation⁴⁹; it also has been shown to decrease mortality in patients with upper-lobe predominant COPD and low exercise capacity.⁵⁰ However, this costly procedure is recommended only in carefully selected patients.⁶ Lung transplantation is a rare therapy for COPD.⁶

Combinations of existing therapies and new pharmacological approaches are available or are currently in development. Data from a randomized, double-blind study of patients with COPD suggest that LABA/LAMA combination treatment may provide improved bronchodilator efficacy versus LABA/ICS combination treatments.⁵¹ “Triple therapy” with a LAMA, LABA, and ICS can improve pulmonary function and COPD symptoms and reduce the rates of exacerbations versus an anticholinergic alone.^6,52-54 The phosphodiesterase-4 inhibitor roflumilast was US FDA-approved in 2011 as an oral medication.⁵⁵ Patients with severe or very severe COPD and a history of exacerbations have fewer moderate or severe exacerbations with roflumilast versus placebo,⁵⁶ regardless of concomitant use of LABAs.⁵⁷ Once-daily LABAs, termed “ultra-LABAs,” such as indacaterol (US FDA-approved in 2011),⁵⁸ may help improve adherence,⁸ although this has not been shown in clinical trials. Ultra-LABA/LAMA combinations (eg, indacaterol/glycopyrronium⁵⁹) are currently in development.

Existing pharmacologic therapies for COPD do not reduce long-term declines in lung function⁶; there is a need for novel therapies that modify disease progression.⁶⁰ Potential approaches for future COPD treatments may include agents that activate histone deacetylase-2 or inhibit phosphoinositide 3-kinase to improve sensitivity to ICS and inhibitors of p38 kinase and cathepsin C to decrease inflammation.⁶⁰

COPD PHENOTYPING

Early studies suggest that COPD clinical subpopulations, such as “frequent exacerbators,” may require more aggressive COPD management earlier in the disease.^61-64 Data from the COPDGene study showed an association between chronic bronchitis and younger age, smoking, worse respiratory symptoms, and a greater history of severe exacerbations.⁶⁵ These findings suggest that for patients with COPD with chronic bronchitis, reducing mucus production and smoking cessation may be extremely important. Other research is ongoing in the Subpopulations and Intermediate Outcomes Measures in COPD Study (Spiromics; http://www.cscc.unc.edu/spir/), the COPDGene Study (http://www.copdgene.org/), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study (http://www.eclipse-copd.com/) assessing mechanisms and identifying potential measures of disease progression.  Historical phenotypes (chronic bronchitis and emphysema)⁶⁶ and those that have been proposed based on clinical manifestations^67-69 are described in Table 2.

CONCLUSIONS

Several pharmacological therapies are available for the treatment of COPD. Current Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend treatment selection according to the patient’s disease severity.⁶ Within a severity category, patient phenotypes and other disease characteristics, device selection, and costs may influence the choice of therapy. Initiation and maintenance of pulmonary rehabilitation programs are important for optimal COPD management in all patients with COPD. Careful monitoring of patients during therapy is necessary to recognize disease worsening and the need for changes in treatment. Improving patient adherence and screening for comorbidities such as depression also contribute to better disease management. In the future, novel therapies may improve bronchodilator efficacy and reduce side effects compared with current treatments and modify disease progression.

Acknowledgments

The author thanks Kristen Quinn, PhD, Anny Wu, PharmD, and Cynthia Gobbel, PhD, from Scientific Connexions (Newtown, PA) who provided medical writing support funded by AstraZeneca LP (Wilmington, DE).

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