Medication has become the mainstay of managing COPD, making it imperative for physicians to have a good understanding of the most effective treatments for improving outcomes in patients with the disease. Along with long-acting anti-cholinergic agents, long-acting β-agonists (LABAs) and inhaled corticosteroids (ICSs) are widely used as combination therapy for COPD. In clinical trials, these drugs have been shown to decrease exacerbations and mortality when compared with placebo. However, few analyses have compared the effectiveness of using LABAs and ICSs in combination with using LABAs alone.

In an effort to address the question of what an ICS adds to a LABA in patients with COPD, Matthew B. Stanbrook, MD, PhD, and colleagues conducted a study that was published in JAMA. “We analyzed 8 years of data on patients aged 66 or older with COPD,” explains Dr. Stanbrook. The study group assessed data on COPD patients who were not on a LABA or ICS at baseline and then either started a LABA alone or were initiated with a LABA plus an ICS. “We followed 3,160 users of LABAs as monotherapy and 8,712 LABA-ICS combination users and then analyzed outcomes that were captured in health service databases,” Dr. Stanbrook says.

Reviewing Results

After controlling for confounders that could influence prescribing decisions, Dr. Stanbrook and colleagues found that LABA-ICS combination therapy reduced mortality risk by about 4% and lowered the risk for COPD-related hospitalizations by about 3% when compared with LABA alone (Table 1). “Although the difference appears to be small on the surface, these are important outcomes for patients with COPD,” says Dr. Stanbrook. “Given the small size of the differences we observed, it would be unlikely that a randomized trial could answer whether outcomes are truly better with LABA alone or LABA-ICS combination therapy. That’s because the power, duration of follow-up, and expenses required to conduct such a trial represent a significant challenge.”

Although the study did not have the rigor of a randomized trial or the freedom from potential confounders that confers, Dr. Stanbrook believes the methodology was the strongest option for answering the question they addressed. “We employed sophisticated epidemiologic methods to correct for potential confounders, including the use of propensity scores,” he says.

The research team also assessed hospitalizations for pneumonia because studies have suggested there is an association between ICSs and the development of the infection. “We did not find an association between ICS and pneumonia,” says Dr. Stanbrook (Table). “We didn’t definitively answer why this was the case. This was partly because our study was an observational analysis. However, this finding raises the hypothesis that a combination of two LABAs may provide enough protection against the increased risk of pneumonia. This approach may mitigate the effect of steroids, but we need more research in this area.”

Dr. Stanbrook and colleagues also assessed the impact of treatments on hospitalizations for hip, wrist, or vertebral fractures. According to the results, there were no important differences in osteoporotic fracture risk between patients who received LABA alone and those who received LABA-ICS combination therapy.

Key Nuances

For the study, Dr. Stanbrook and colleagues pre-specified two key factors that may modify the effect of ICSs: 1) whether or not patients had asthma, and 2) whether or not patients had already been treated with a long-acting anti-cholinergic medication. “Among patients with asthma, the benefits seen with ICSs were higher, regardless of whether or not they were also taking a long-acting anticholinergic agent,” says Dr. Stanbrook. “For patients without asthma, ICSs were only beneficial among those who were not also taking a long-acting anticholinergic agent. This is important because about one-third of all COPD patients have asthma-COPD overlap syndrome.”

Whether or not patients had undergone spirometry was also assessed at baseline. “In many cases, COPD patients get diagnosed without any form of objective pulmonary function testing,” explains Dr. Stanbrook. “Therefore, it may be reasonable to expect that patients who were objectively classified as having COPD to respond differently to ICSs. However, we did not find that a spirometry-based diagnosis of COPD played a significant role in patient outcomes.” He adds that the slightly greater benefit seen in patients who did not undergo spirometry suggests that these individuals had more pure COPD rather than asthma-COPD overlap syndrome.

Important Implications

“Few interventions have been shown to reduce mortality in COPD,” says Dr. Stanbrook. “Our finding that adding an ICS to LABA therapy has the potential to reduce mortality is important because clinicians can use this information to tailor therapy to appropriate populations, including those with asthma-COPD overlap syndrome.”