Case-Based Review

Management of Stable Chronic Obstructive Pulmonary Disease

Journal of Clinical Outcomes Management. 2017 June;24(6)

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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].