COPD: Optimizing treatment

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, however, 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 FEV₁ 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 FEV₁ (>120 mL; P<.01), regardless of the dose administered.^6,16 In another trial, patients taking aclidinium 200 mcg or 400 mcg every 12 hours did not achieve a clinically significant improvement in FEV₁ 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 FEV₁ (167 mL; P<.001) vs placebo—but was not significantly better than treatment with either agent alone.¹⁸

Long-acting inhaled anticholinergic agents—when used in combination with LABAS—have a positive effect on FEV₁, but their effect on exacerbation rates has not been established.

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 FEV₁, 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 FEV₁ 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 FEV₁,²⁴ 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

In one study, patients slowly withdrawn from oral corticosteroids had no more frequent exacerbations than those who maintained chronic usage.

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 FEV₁ 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