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Study Authors: Claudia C. Dobler, Allison S. Morrow, et al.

Target Audience and Goal Statement: Pulmonologists, infectious disease specialists, emergency department physicians, hospitalists

The goal of this study was to evaluate the comparative effectiveness and adverse events (AEs) of pharmacologic interventions for adults with exacerbation of chronic obstructive pulmonary disease (COPD).

Question Addressed:

• What were the effects of pharmacologic interventions on health outcomes and AEs in adults with exacerbation of COPD?

Study Synopsis and Perspective:

Shortness of breath, cough, and sputum production are hallmark symptoms of COPD — a progressive, debilitating respiratory condition with an estimated global prevalence of 251 million cases, according to 2016 estimates. In the U.S., COPD affects at least 15 million people, is the third leading cause of death, and costs more than $32 billion per year.

According to the latest Global Initiative for Chronic Obstructive Lung Disease (GOLD) report, disease management goals are to determine the level of airflow limitation, the impact of disease on the patient’s health status, and the risk of future events (such as acute worsening of respiratory symptoms known as exacerbations, hospitalizations, and death), and to prevent subsequent events.

Once the severity of airflow limitation has been established via spirometry within a relevant clinical context, supportive care with maintenance therapies are important in managing stable COPD. However, respiratory viral/bacterial infections and environmental factors might trigger flare-ups. GOLD classifies exacerbations as:

• Mild (treated with short-acting bronchodilators [SABDs] only)
• Moderate (treated with SABDs plus antibiotics and/or oral corticosteroids)
• Severe (patient requires hospitalization/visit to an emergency room; also associated with respiratory failure)

Most exacerbation cases (80%) are managed on an outpatient basis with pharmacologic therapies, including bronchodilators, antibiotics, and corticosteroids. Nevertheless, initial treatment is unsuccessful in 24% to 27% of patients, who have a relapse or a second exacerbation within 30 days of the initial event.

It remains unclear whether COPD patients with exacerbations, especially those with mild events treated as outpatients, would benefit from treatment with antibiotics and systemic corticosteroids. Also unclear is whether combining different SABDs (short-acting beta-adrenergic agonists and short-acting muscarinic antagonists) or using either agent alone would relieve dyspnea and improve airflow obstruction during an exacerbation. Additionally, the benefits of other pharmacologic interventions for the management of exacerbations of COPD have not been fully explored.

Answering these important questions will help in terms of reducing antibiotic prescriptions, where safely possible, to decrease potential harms, including development of antibiotic resistance, and to reduce potentially significant AEs from systemic corticosteroids, in particular hyperglycemia, in patients with glucose intolerance and diabetes, according to an earlier systematic review.

Therefore, Claudia C. Dobler, MD, PhD, of the Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery at the Mayo Clinic in Rochester, Minnesota, and colleagues performed a systematic review and meta-analysis of 68 randomized controlled trials that enrolled adults with exacerbation of COPD treated in out- or inpatient settings other than intensive care and compared pharmacologic therapies with placebo, usual care, or other pharmacologic interventions. They published their results in Annals of Internal Medicine.

While treatment setting was unclear for six trials, patients treated in the outpatient setting (n=19), emergency department (n=10), hospital (n=31), and mixed outpatient and hospital setting (n=1) were represented in the remainder of the trials. Treatment and follow-up ranges were 4 to 56 days and 1 to 12 days, respectively. Roughly two-thirds of the trials (65% [44 of 68 trials]) reported AEs. The researchers did not find associations between interventions and statistically significant increases in serious AEs.

Antibiotics given for 3 to 14 days were associated with increased exacerbation resolution (odds ratio [OR] 2.03, 95% CI 1.47-2.80, moderate strength of evidence [SOE]) and fewer treatment failures at the end of the intervention (OR 0.54, 95% CI 0.34-0.86, moderate SOE) compared with placebo or management without antibiotics. Results were independent of exacerbation severity in out- and inpatients.

Systemic corticosteroids given for 9 to 56 days were associated with fewer treatment failures at the end of the intervention (OR 0.01, 95% CI 0.00-0.13, low SOE). However, they were also associated with a statistically significantly higher number of total AEs and endocrine-related AEs.

“Compared with placebo or usual care in inpatients, other pharmacologic interventions (aminophyllines, magnesium sulfate, anti-inflammatory agents, inhaled corticosteroids, and short-acting bronchodilators) had insufficient evidence, showing either no or inconclusive effects (with the exception of the mucolytic erdosteine) or improvement only in lung function,” the researchers wrote.

Study limitations included the inclusion of only a single trial or two trials for certain drug interventions, “which limits inference from the quantitative synthesis,” as well as the exclusion of trials that were published in languages other than English. Since most studies focused on hospitalized patients with moderate to severe exacerbations, the results might not be applicable to patients with milder forms of exacerbation treated in an outpatient setting. Similarly, patients in intensive care units were excluded from the study, which means that the results may not be applicable to some of the sickest patients.

Source Reference: Annals of Internal Medicine 2020; DOI: 10.7326/M19-3007

Study Highlights and Explanation of Findings:

Based on the current systematic review and meta-analysis, use of antibiotics and systemic corticosteroids was associated with lower rates of treatment failure (independent of exacerbation severity) and improved dyspnea at the end of the intervention compared with placebo or management without these interventions. However, there was insufficient or no evidence informing the optimal choice of antibiotic or corticosteroid treatment regimens (agent type, dosage, application route, or duration of treatment).

These findings supported previous systematic reviews, including an earlier systematic review conducted to inform the most recent European Respiratory Society/American Thoracic Society joint guidelines, which found antibiotics to be beneficial in the treatment of COPD exacerbations. Dobler and team noted that the current review included three additional trials in which outpatients with mild to moderate exacerbation of COPD had a decreased risk for treatment failure with antibiotics.

In an interview with MedPage Today, co-author Michael E. Wilson, MD, also of the Mayo Clinic, noted that in clinical practice, antibiotics are often not given to patients with mild exacerbations unless they have symptoms, such as high sputum production or frequent cough.

“If patients are not experiencing these symptoms, [clinicians] may be inclined to manage exacerbations with steroids and bronchodilator without antibiotics,” he said. “This review would suggest that patients with mild, as well as moderate and severe, exacerbations may benefit from treatment with antibiotics even if they don’t have these symptoms.”

The present systematic review and meta-analysis also included three studies that indicated that different durations of systemic corticosteroid treatment (3 vs 10 days; 5 vs 14 days; 2 vs 8 weeks) did not show better improvement in exacerbation outcomes with the longer treatment regimens. These findings support the use of shorter regimens of systemic corticosteroids.

In addition, inhaled corticosteroids were noninferior to systemic corticosteroids for clinically important outcomes — a finding that was similar to a previous systematic review that found no statistically significant difference in surrogate outcomes.

The researchers mentioned several ongoing randomized trials that could inform the treatment of COPD exacerbations, including NCT02294734, NCT04075331, and NCT04098718.

“Our review found a lack of good-quality, reliable evidence to answer many of the important clinical questions surrounding treatment of patients with exacerbation of COPD,” they concluded. “Future studies should focus on high-quality study design and patient-centered outcomes — particularly clinical resolution of exacerbation and risk for repeated exacerbation, rather than lung function measurements.”

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