Fluticasone propionate/salmeterol 250/50 μg versus salmeterol 50 μg after chronic obstructive pulmonary disease exacerbation

Abstract

Background: Inhaled long-acting beta2 agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD. However, the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known. This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol (FP/SAL) or SAL alone.

Methods: Patients (n = 639) aged ≥40 years were randomized to either twice-daily inhaled FP/SAL 250/50 μg or SAL 50 μg. Primary, and secondary, endpoints were rates of recurrent severe, and moderate/severe, exacerbations of COPD. Lung function, health outcomes and levels of biomarkers of systemic inflammation were also assessed.

Results: There was no statistically significant treatment difference in rates of recurrent severe exacerbations (treatment ratio 0.92 [95% CI: 0.58, 1.45]) and moderate/severe exacerbations (0.82 [0.64, 1.06]) between FP/SAL and SAL in the intent-to-treat population. Pre-dose morning FEV1 change from baseline was greater (0.10 L [0.04, 0.16]) with FP/SAL than SAL. No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort.

Conclusions: No significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort. Treatment benefit with FP/SAL over SAL (treatment ratio 0.68 [0.47, 0.97]) was seen in patients having FEV1 ≥ 30% and prior exposure to ICS. No unexpected safety issues were identified with either treatment. Patients with the most severe COPD may be more refractory to treatment.

Trial registration: ClinicalTrials.gov (identifier NCT01110200). This study was funded by GlaxoSmithKline (study number ADC113874).

Figure 1

Chronological schematic of experimental design. Note: 1. Duration of index hospitalization is ≤10 days. Time from hospital discharge, ER, or physician’s office visit (due to the recent exacerbation) to Randomization (Visit 2) is ≤14 days. Visit 1 (Screening) and Visit 2 can occur during the hospitalization, ER visit, physician’s office visit, and up to 14 days afterward. 2. Duration of subjects’ participation in study is 29 weeks (completing subjects), approximately (unless subject is prematurely withdrawn from the study). ER: Emergency Room; F/U: Follow-up; TC: Telephone call; V: Visit; Wks: Weeks.

Figure 2

Patient disposition and reasons for study withdrawal. FP = fluticasone propionate; SAL = salmeterol.

Figure 3

Kaplan-Meier estimates for A) time to first COPD exacerbation requiring oral corticosteroids, antibiotics and/or hospitalization, and B) time to withdrawal from study, over 26 weeks of treatment following the 3-week stabilization period, ITT population. COPD = chronic obstructive pulmonary disease; FP = fluticasone propionate; ITT = intent-to-treat; SAL = salmeterol.

Figure 4

Overall numbers of exacerbations by 4-week period, over 26 weeks of treatment following the 3-week stabilization period, ITT population. *Weeks from end of 21-day stabilization period. FP = fluticasone propionate; ITT = intent-to-treat; SAL: salmeterol.

Figure 5

Summary of pre-dose morning FEV ₁ during the 3-week stabilization period, over Weeks 0–26, and at endpoint, ITT population. FEV₁ = forced expiratory volume in one second; FP = fluticasone propionate; ITT = intent-to-treat; SAL = salmeterol.