Management of Stable Chronic Obstructive Pulmonary Disease
As far as efficacy and benefits, tiotropium and salmeterol were compared head-to-head in a clinical trial, and tiotropium increased the time before developing first exacerbation and decreased the overall rate of exacerbations [37]. No difference in hospitalization rate or mortality was noted in one meta-analysis, although tiotropium was more effective in reducing exacerbations [38]. The choice of agent should be made based on patient comorbidities and side effects. For example, an elderly patient with severe benign prostatic hyperplasia and urinary retention should try a LABA while for a patient with severe tachycardia induced by albuterol, LAMA would be a better first agent.
What is the role of inhaled corticosteroids in COPD?
Inhaled corticosteroids (ICS) are believed to work in COPD by reducing airway inflammation [39]. ICS should not be used alone for COPD management and are always combined with LABA [7]. Several inhaled corticosteroid formulations are approved for use in COPD, including budesonide and fluticasone. ICS has been shown to decrease symptoms and exacerbations with modest effect on lung function and no change in mortality [40]. Side effects include oral candidiasis, dysphonia, and skin bruising [41]. There is also an increased risk of pneumonia [42]. ICS are best reserved for patients with a component of asthma or asthma–COPD overlap syndrome (ACOS) [43]. ACOS is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD [44].
What if the patient is still symptomatic on a LABA or LAMA?
For patients whose symptoms are not controlled on one class of long-acting bronchodilator, recommendations are to add a bronchodilator from the other class [7]. There are also multiple combined LAMA-LABA inhalers that are approved in the US and can possible improve adherence to therapy. These include tiotropium-oladeterol, umeclidinium-vilanterol, glycopyronnium-indacaterol, and glycopyrrolate-formoterol. In a large systematic review and meta-analysis comparing LABA-LAMA combination to either agent alone, there was a modest improvement in post bronchodilator FEV1 and quality of life with no change in hospital admissions, mortality, or side effects [45]. Interestingly, adding tiotropium to LABA reduced exacerbations although adding LABA to tiotropium did not [45].
Current guidelines recommend that patients in GOLD categories C and D that are not well controlled should receive a combination of LABA-ICS [7]. However, a new randomized trial showed better reduction of exacerbations and decreased occurrence of pneumonia in patients receiving LAMA-LABA compared to LABA-ICS [46]. In light of this new evidence, it is prudent to use a LAMA-LABA combination before adding ICS.
Triple therapy with LAMA, LABA, and ICS is a common approach for patients with severe uncontrolled disease and has been shown to decrease exacerbations and improve quality of life [7,47]. Adding tiotropium to LABA-ICS decreased exacerbations and improved quality of life and airflow in the landmark UPLIFT trial [26]. In another clinical trial, triple therapy with LAMA, LABA, and ICS compared to tiotropium alone decreased severe exacerbations, pre-bronchodilator FEV1, and morning symptoms [48].
Is there a role for theophylline? Other agents?
Theophylline
Theophylline is an oral adenosine diphosphate antagonist with indirect adrenergic activity, which is responsible for the bronchodilator therapeutic effect in patients with obstructive lung disease. It is also thought to work by an additional mechanism that decreases inflammation in the airways [49]. It has a serious side effect profile that includes ventricular arrhythmias, seizures, vomiting, and tremor [50]. It is metabolized in the liver and has multiple drug interactions and a narrow therapeutic index. It has been shown to improve lung function, gas exchange and symptoms in meta-analysis and clinical trials [51,52].
In light of the nature of the adverse effects and the wide array of safer and more effective pharmacologic agents available, theophylline should be avoided early on in patients with COPD. Its use can be justified as an add-on therapy in patients with refractory disease on triple therapy for symptomatic relief [50]. If used, the therapeutic range for COPD is 8–12 mcg/mL peak level measured 3 to 7 hours after morning dose and is usually achieved using a daily dose of 10 mg per kilogram of body weight for nonobese patients [53].
Systemic Steroids
Oral steroids are used in COPD exacerbations but should never be used chronically in COPD patients regardless of disease severity as they increase morbidity and mortality without improving symptoms or lung function [54,55]. The dose of systemic steroids should be tapered and finally discontinued.
Mucolytics
Classes of mucolytics include thiol derivatives, inhaled dornase alpha, hypertonic saline, and iodine preparations. Thiol derivatives such as N-acetylcysteine are the most widely studied [56].
There is no consistent evidence of beneficial role of mucolytics in COPD patient [7,56]. The PANTHEON trial showed decreased exacerbations with N-acetylcysteine (1.16 exacerbations per patient-year compared to 1.49 exacerbations per patient-year in the placebo group; risk ratio 0.78, 95% CI 0.67–0.90; P = 0.001) but had methodologic issues including high drop-out rate, exclusion of patients on oxygen, and a large of proportion of nonsmokers [57].
Chronic Antibiotics
There is no role for chronic antibiotics in the management of COPD [7]. Macrolides are an exception but are used for their anti-inflammatory effects rather than their antibiotic effects. They should be reserved for patient with frequent exacerbations on optimal therapy and will be discussed later in the review [58].
What nonpharmacologic treatments are recommended for COPD patients?
Smoking cessation, oxygen therapy for severe hypoxemia (resting O2 saturation ≤ 88 or PaO2 ≤ 55), vaccination for influenza and pneumococcus, and appropriate nutrition should be provided in all COPD patients. Pulmonary rehabilitation is indicated for patients in GOLD categories B, C, and D [7]. It improves symptoms, quality of life, exercise tolerance and health care utilization. Beneficial effects last for about 2 years [59,60].
What other diagnoses should be considered in patients who continue to be symptomatic on optimal therapy?
Other diseases that share the same risk factors as COPD and can contribute to dyspnea, including coronary heart disease, heart failure, thromboembolic disease, and pulmonary hypertension, should be considered. In addition, all patients with refractory disease should have a careful assessment of their inhaler technique, continued smoking, need for oxygen therapy, and associated deconditioning.
