Pharmacotherapy and Lung Function Decline in Patients with Chronic Obstructive Pulmonary Disease. A Systematic Review.

Rationale: Whether pharmacological therapy alters decline in FEV1 in chronic obstructive pulmonary disease remains controversial. Because pharmacotherapy improves health status, exacerbation rate, and symptoms, it may be unethical to complete placebo-controlled long-term studies aimed at modifying FEV1 decline.Objectives: We conducted a systematic review of placebo-controlled pharmacological trials lasting ≥1 year to address the question of whether therapy alters FEV1 decline.Methods: A literature search for randomized trials that included repeated spirometry with at least one active and one placebo arm was conducted. Articles were excluded if study duration was <1 year, <3 spirometric measurements, or <100 subjects per arm. Study design was assessed using the Jadad score. To combine studies and find the estimated effect, we used random effects methodology to account for both within-study and between-study variation.Measurements and Main Results: There were 33,051 patients in the analysis (active component, n = 21,941; placebo, n = 11,110 in nine studies). The active treatment arms demonstrated a 5.0 ml/yr reduction (95% confidence interval, 0.8-9.1 ml/yr; P < 0.001) in the rate of FEV1 decline compared with the placebo arms. The relative FEV1 differences between active and placebo arms were within the range of differences reported for health status and for the exacerbation rate in the same studies.Conclusions: In chronic obstructive pulmonary disease, pharmacotherapy ameliorates rate of lung function decline. The relative benefit observed is within the range of those reported for health status and exacerbations in the same studies. Guidelines should be adjusted according to these findings.

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

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).

Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD.

BACKGROUND: Combining maintenance medications with different mechanisms of action may improve outcomes in COPD. In this study we evaluated the efficacy and safety of fluticasone/salmeterol (FSC) (250/50 mcg twice daily) when added to tiotropium (18 mcg once daily) (TIO) in subjects with symptomatic moderate to severe COPD. METHODS: This was a 24-week, randomized, double-blind, parallel group, multi-center study. Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV(1) ≥40 to ≤ 80% of predicted normal and FEV(1)/FVC of ≤0.70 were enrolled. Following a 4-week treatment with open-label TIO 18 mcg once daily, subjects were randomized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo. The primary efficacy endpoint was AM pre-dose FEV(1) and secondary endpoints included other measures of lung function, rescue albuterol use, health status and exacerbations. RESULTS: The addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV(1), 2 h post-dose FEV(1), AM pre-dose FVC, 2 h post-dose FVC and AM pre-dose IC compared with TIO alone. Furthermore, this combination was superior to TIO alone in reducing rescue albuterol use. However, there were no significant differences between the treatment groups in health status or COPD exacerbations. The incidence of adverse events was similar in both groups. CONCLUSIONS: The addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events. NCT00784550.