Treating COPD Patients with a History of Frequent Exacerbations

Optimal protocol for each individual remains unclear

By Umur Hatipoğlu, MD

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Exacerbations of COPD, defined by worsening of the cardinal symptoms of COPD beyond day-to-day variations, represent acute inflammatory states superimposed on chronic inflammation. Exacerbations generally include acute increase in cough severity and frequency, increase in sputum production, change in sputum character or increase in dyspnea.

Exacerbations negatively impact quality of life and have been linked to poor clinical outcomes, including more rapid lung function decline and higher mortality rates. Cost to the healthcare system is substantial. Therefore, implementation of preventive measures during the stable state is crucial.

Therapeutic options to consider

Fortunately, multiple pharmacotherapeutic options are available to meet this need. They include:

  • Long-acting anti-muscarinic agents
  • Long-acting beta2-agonists
  • Combination therapy (long-acting antimuscarinic agent + inhaled corticosteroid)
  • Dual bronchodilators (long-acting antimuscarinic agent + long-acting beta2-agonist)
  • Triple therapy (long-acting anti-muscarinic agent + long-acting beta2-agonist + inhaled corticosteroid)
  • PDE4 inhibitor
  • Macrolides
  • Mucolytics

Long-acting antimuscarinic agents are considered first-line treatment for the prevention of exacerbations. These agents have proven superior to long-acting beta2-agonists and equivalent to combination therapy. Recently, the FLAME trial showed a 17 percent reduction in moderate-to-severe exacerbations with dual bronchodilator therapy compared with combination therapy in COPD patients with one exacerbation in the previous year.

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The utility of using combination therapy plus long-acting antimuscarinic agent together—so-called triple therapy—is not yet clear. In the WISDOM trial, gradually withdrawing inhaled corticosteroids from triple therapy was not associated with increased exacerbation rate overall.  However, a small increase in severe exacerbations and lower lung function and decrease in quality of life was seen in a subset of patients.

For preventing exacerbations using existing inhaled therapy options, step-up therapy starting with a long-acting anti-muscarinic agent and adding a long-acting beta-2 agonist seems reasonable. However, patients with eosinophilic inflammation (“asthma-COPD overlap syndrome”), poor lung function and low quality of life are more likely to benefit from inhaled corticosteroids.

Oral options for exacerbation prevention

Oral options for exacerbation prevention include the PDE4 inhibitor roflumilast, the macrolide azithromycin and mucolytics. Roflumilast may reduce exacerbations further when added to triple therapy in patients with COPD and chronic bronchitis, frequent exacerbations and poor lung function (defined as FEV1 less than 50 percent). In the post hoc analysis of the RESPOND trial, patients with three or more exacerbations or hospitalization in the previous year experienced a 39 percent and 25 percent lower rate of exacerbations, respectively, when roflumilast was added to combination therapy.

Long-term azithromycin therapy may reduce exacerbations of COPD, although no impact on hospitalizations has been reported. The enthusiasm for this modality has been tempered by the relatively high risk of hearing loss, potential for prolonged QTc interval and emergence of bacterial resistance.

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Mucolytic treatment may have a role in relieving symptoms, particularly among patients with chronic bronchitis exhibiting thick, tenacious sputum. In a Chinese study, twice-daily N-acetylcysteine added to optimal pharmacotherapy was shown to reduce mild-to-moderate exacerbations, without affecting hospitalization rates.

Optimal choice for different phenotypes still unclear

The optimal agent to use in a particular type of patient, and in what sequence or combination, remains an important question. In the future, phenotyping may be helpful in this regard. According to the GOLD guidelines, patients with COPD may be grouped according to symptom burden and frequency and degree of lung impairment.  Exacerbations can also be phenotyped according to the nature of inflammation (bacterial, viral, eosinophilic, pauci-immune [absent inflammatory biomarkers] or of mixed etiology). GOLD guidelines do not yet include guidance on the approach to treatment and prevention of different exacerbation phenotypes.

Clearly, great progress in the pharmacotherapeutic prevention of COPD exacerbations has been made over the past two decades. In the future, clinical trials are likely to include COPD populations enriched for different phenotypes in the search for tailored therapies. In the meantime, clinicians should utilize individual clinical assessment and consideration of existing guidelines in directing therapy.

Dr. Hatipoglu is staff in the Department of Pulmonary Medicine and Quality Improvement Officer in the Respiratory Institute.