Use and Comparative Safety of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease

Objectives: Roflumilast is indicated for patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD). The extent of use and safety of roflumilast in the real-world clinical practice is limited. Therefore, this study aims to describe the use and comparative safety of roflumilast in patients with COPD. Methods: We identified a cohort of patients aged ≥40 years diagnosed with COPD who newly initiated roflumilast from March 2010 to September 2018 in the Truven MarketScan database. We measured demographic and clinical characteristics in the 12-month period prior to first date of use, the index date. Adherence was measured using prescription days covered (PDC) ≥ 80% threshold over a 6-month period. We calculated persistence as the proportion of patients that continued using roflumilast, defined as a prescription claim gap of ≤ 30 days. Next we identified new users of roflumilast and the active comparator group, triple therapy (inhaled corticosteroids (ICS), long acting beta agonists (LABA) and long acting muscarinic antagonists (LAMA)). The safety outcomes were a diagnosis of non-infectious diarrhea and anxiety/depression within 30 days after treatment initiation. We estimated adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) for diarrhea. Follow-up continued to the earliest of the occurrence of the outcome of interest (diarrhea), treatment discontinuation, end of 30-day follow-up, disenrollment from health plan or end of study period. We used high-dimensional propensity score (hdPS) matching and calculated the E-value to quantify unmeasured confounding. Results: The mean age was 68 years (±10) and 50% were female. The overall PDC over a 6-month period was 69% with only 3104 (48.8%) patients being adherent (PDC≥ 80%). Roflumilast users had higher risk of diarrhea over the 30-day period after drug initiation relative to the comparator group [RR=2.10, 95%CI (1.25, 3.54)]. A similarly higher risk of the outcome occurred in the roflumilast group at 60 days [RR=1.50, 95%CI (1.00, 2.26)] and at 90 days [RR=1.45, 95% CI (1.05, 2.02)].The corresponding E-values for the primary analysis of 30 days period were 3.62 and 1.81 for the RR and lower bound of the CI respectively. We found no significantly elevated risk of anxiety or depression at 30 days [RR=1.03, 95%CI (0.71, 1.49)], 90 days [RR=0.92, 95%CI (0.75, 1.19)] and 180 days [RR=0.94, 95%CI (0.79, 1.12)]. Conclusions: A substantial number of adult patients with COPD have sub-optimal adherence and persistence to roflumilast. We observed a higher risk of diarrhea and no significantly elevated risk of anxiety and depression among patients initiating roflumilast compared to those taking triple therapy (ICS, LAMA and LAMA) in the real-world settings.