Roflumilast Associated with Increase in 5-Year Mortality Risk in Patients with COPD

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A small 5-year mortality risk increase was observed among patients with chronic obstructive pulmonary disease (COPD) in Germany and the US who used roflumilast but not among those in Sweden or Norway, according to a study published in the International Journal of Chronic Obstructive Pulmonary Disease.¹

Currently, patients with COPD have a reported 5-year mortality rate of 24.5%.² COPD is often complicated by chronic bronchitis (CB), which is associated with the worsening of respiratory symptoms and more frequent exacerbations³; it also further increases the high mortality risk. The researchers noted that pharmacotherapy plays a crucial role in COPD management, helping improve symptoms and health status while decreasing the frequency and severity of exacerbations.

Current COPD pharmacologic agents include inhaled corticosteroids, long-acting muscarinic antagonists, and long-acting β-agonists.¹ Roflumilast, a selection phosphodiesterase-4 inhibitor, was licensed in 2010 as a last-line add-on therapy to treat those with severe COPD, CB, and a history of exacerbations when standard therapies are not sufficient to alleviate symptoms.⁴

Various clinical trials have proven the efficacy of roflumilast among patients with severe COPD and CB.¹ However, data are limited on its long-term safety in real-world studies or clinical trials. Consequently, the researchers conducted a study to address this knowledge gap, focusing on 5-year all-cause mortality among patients with COPD and CB receiving roflumilast in a real-world setting.

The researchers used data from electronic health care databases in 4 countries. More specifically, they used nationwide registries from Sweden and Norway and medical claims databases from Germany (German Pharmacoepidemiological Research Database) and the US (Military Health System). All databases contain historical data for patient care and drug dispensations.

The study period began on the roflumilast launch in each country and ended on December 31, 2018. The researchers matched patients 40 years or older with COPD or CB with a first-time roflumilast exposure in one of the cohort entry years (2010-2013; exposed cohort) to roflumilast-unexposed patients with COPD or CB (unexposed cohort).

Matching was based on age, sex, propensity score (PS), and calendar year of the cohort entry date (CED); PS included variables like demographics, comorbidities, and markers of COPD severity and morbidity. Exposed patients were matched with up to 5 unexposed patients, and each yearly cohort was followed up for at least 5 years.

The main outcome analyzed was 5-year all-cause mortality. The researchers also used 3 exposure definitions to compare the exposed and unexposed cohorts: ever use, use status (current, recent, past use), and cumulative duration of use.

After matching, the study population consisted of 135 856 patients, with 23 239 in the exposed cohort. More specifically, the study population contained 50 567 German patients (8783 exposed patients), 9472 Norwegian patients (1624 exposed patients), 19 025 Swedish patients (3234 exposed patients), and 56 792 American patients (9598 exposed patients). The researchers noted that age and sex were balanced in the matched cohorts at CED after matching, but not all COPD severity and morbidity variables were balanced.

They found that comparing the “ever use” and “never use” cohorts resulted in a small increase in 5-year all-cause mortality rates among patients in Germany (adjusted HR [aHR], 1.12; 95CI, 1.08-1.17) and the US (aHR, 1.16; 95% CI, 1.12-1.20). No difference in mortality risk was observed among those in Norway (aHR, 1.00; 95% CI, 0.92-1.08) or Sweden (aHR, 0.98; 95% CI, 0.92-1.04).

Similarly, there was no elevated mortality risk across the countries when comparing the current use and never use cohorts. More specifically, a decrease in mortality risk was observed among current roflumilast users in Germany (aHR, 0.93; 95% CI, 0.88-0.99), Norway (aHR, 0.77; 95% CI, 0.67-0.87), and Sweden (aHR, 0.80; 95% CI, 0.73-0.88).

However, an increase in mortality risk was found among the recent use cohort compared with the never use cohort in Germany, Norway, and the US. Similarly, among the past use cohort, an increase in mortality was seen in all countries compared with the never use cohort.

Lastly, the researchers found no association between the cumulative use categories and 5-year all-cause mortality among the patients in Norway and Sweden. In Germany, no increased mortality risk was observed in patients who used roflumilast for more than 24 months. However, an increased mortality risk was identified in German patients who used roflumilast for shorter cumulative durations (3-12 months or 12-24 months). As for the US, a significant rise in mortality risk was observed across all cumulative use categories.

The researchers acknowledged limitations on their findings, including the limited capture of COPD severity and morbidity variables across the utilized databases. However, they also highlighted their study’s strengths, like its long follow-up and generalizability.

“Our study included 5 years of follow-up, allowing for the assessment of long-term effects of roflumilast as well as the impact of long-term exposure to the treatment,” the authors wrote. “The generalizability of the study results is supported by its real-world setting and by the representativeness of its data from the Norwegian and Swedish national registries and large population samples from Germany and the US.”

References

1. Garbe E, Hoti F, Schink T, et al. Long-term safety of roflumilast in patients with chronic obstructive pulmonary disease, a multinational observational database cohort study. Int J Chron Obstruct Pulmon Dis. 2024;19:1879-1892. doi:10.2147/COPD.S465517

2. Park SC, Kim DW, Park EC, et al. Mortality of patients with chronic obstructive pulmonary disease: a nationwide population-based cohort study. Korean J Intern Med. 2019;34(6):1272-1278. doi:10.3904/kjim.2017.428

3. Lahousse L, Seys LJM, Joos GF, Franco OH, Stricker BH, Brusselle GG. Epidemiology and impact of chronic bronchitis in chronic obstructive pulmonary disease. Eur Respir J. 2017;50(2):1602470. doi:10.1183/13993003.02470-2016

4. Giembycz MA, Field SK. Roflumilast: first phosphodiesterase 4 inhibitor approved for treatment of COPD. Drug Des Devel Ther. 2010;4:147-158. Published 2010 Jul 21. doi:10.2147/dddt.s7667