Stable COPD: Managing Acute Exacerbations

Pulmonary Disease Board Review. 2019 July;16(1)

From the University of Florida, Gainesville, FL (Dr. Aljaafareh and Dr. Fakih), and Parkview Regional Medical Center, Fort Wayne, IN (Dr. Biswas).

References

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What are the pharmacologic options available for prevention of AECOPD?

In recognition of the importance of preventing COPD exacerbations, the American College of Chest Physicians and Canadian Thoracic Society⁵ have published an evidence-informed clinical guideline specifically examining the prevention of AECOPD, with the goal of assisting clinicians in providing optimal management for COPD patients. The following pharmacologic agents have been recognized as being effective at reducing the frequency of acute exacerbations without any impact on the severity of COPD itself.

Roflumilast

Phosphodiesterase 4 (PDE4) inhibition appears to have inflammatory-modulating properties in the airways, although the exact mechanism of action is unclear. Some have proposed that it reduces inflammation by inhibiting the breakdown of intracellular cyclic adenosine monophosphate.¹³ In 2 large clinical trials,^14,15 daily use of a PDE4 inhibitor (roflumilast) showed a significant (15%–18%) reduction in yearly AECOPD incidence (approximate number needed to treat: 4). This benefit was seen in patients with GOLD stage 3–4 disease (FEV₁ < 50% predicted) with the chronic bronchitic phenotype and who had experienced at least 1 exacerbation in the previous year.

Importantly, these clinical trials specifically prohibited the use of inhaled corticosteroids (ICS) and long-acting muscarinic antagonists (LAMAs). Thus, it remains unclear if PDE4 inhibition should be used as an add-on to ICS/LAMA therapy in patients who continue to have frequent AECOPD or whether PDE4 inhibition could be used instead of these standard therapies in patients with well-controlled daily symptoms without ICS or LAMA therapy but who experience frequent exacerbations.

Of note, earlier trials with roflumilast included patients with ICS and LAMA use.^14,16 These trials were focused on FEV₁ improvement and found no benefit. It was only in post ad hoc analyses that a reduction in AECOPD in patients with frequent exacerbations was found among those taking roflumilast, regardless of ICS or LAMA use.¹⁷ While roflumilast has documented benefit in improving lung function and reducing the rate of exacerbations, it has not been reported to decrease hospitalizations.⁴ This indicates that although the drug reduces the total number of exacerbations, it may not be as useful in preventing episodes of severe exacerbations of COPD.

Although PDE4 inhibitors are easy to administer (a once-daily pill), they are associated with significant gastrointestinal side effects (diarrhea, nausea, reduced appetite), weight loss, headache, and sleep disturbance.¹⁸ Adverse effects tend to occur early during treatment, are reversible, and lessen over time with treatment.⁶ Studies reported an average unexplained weight loss of 2 kg, and monitoring weight during treatment is advised. In addition, it is important to avoid roflumilast in underweight patients. Roflumilast should also be used with caution in depressed patients.⁵

N-acetylcysteine

N-acetylcysteine (NAC) reduces the viscosity of respiratory secretions as a result of the cleavage of the disulfide bonds and has been studied as a mucolytic agent to aid in the elimination of respiratory secretions.¹⁹ Oral NAC is quickly absorbed and is rapidly present in an active form in lung tissue and respiratory secretions after ingestion. NAC is well-tolerated except for occasional patients with GI adverse effects. The role of NAC in preventing AECOPD has been studied for more than 3 decades,^20-22 although the largest clinical trial to date was reported in 2014.²³ Taken together, the combined data demonstrate a significant reduction in the rate of COPD exacerbations associated with the use of NAC when compared with placebo (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.37-0.99). Clinical guidelines suggest that in patients with moderate to severe COPD (FEV₁/forced vital capacity ratio < 0.7, and FEV₁ < 80% predicted) receiving maintenance bronchodilator therapy combined with ICS and history of 2 more exacerbations in the previous 2 years, treatment with oral NAC can be administered to prevent AECOPD.