Association Between FEV₁ Decline Rate and Mortality in Long-Term Follow-Up of a 21-Patient Pilot Clinical Trial of Inhaled Liposomal Cyclosporine Plus Standard-of-Care Versus Standard-of-Care Alone for Bronchiolitis Obliterans Syndrome After Lung Transplantation

Abstract

BACKGROUND The association between forced expiratory volume in 1 second (FEV1) trajectory and mortality in bronchiolitis obliterans syndrome (BOS) is not well defined. Using long-term data from a prior clinical trial of inhaled liposomal cyclosporine A (L-CsA-I) for lung transplant patients with BOS, this study examined the association between longitudinal FEV₁ change and mortality. MATERIAL AND METHODS We analyzed long-term data from a clinical trial which randomized 21 patients with BOS (³20% decrease in FEV1 from personal maximum) to receive L-CsA-I plus standard-of-care (n=11) or standard-of-care (SOC) alone (n=10) for 24 weeks. A joint statistical model, combining a linear mixed model for FEV₁ change and Cox regression for mortality, was utilized to examine the overall association between FEV₁ trajectory and mortality during follow-up. RESULTS The 21 trial participants (10 single, 11 double lung recipients) had a mean FEV₁ of 1.7±0.6 Liters at randomization. Median follow-up post-randomization was 35 months. In joint model analysis, 1 percent FEV₁ decline predicted 1.076-fold increased mortality risk (95% confidence interval: -0.998 to 1.160, p=0.058). FEV₁ decline was reduced by 2.6% per year in L-CsA-I patients compared to SOC (p=0.210), and overall survival at 1/3/5 years was 91%/64%/27% vs 90%/20%/0% for L-CsA-I versus SOC, respectively (p=0.164). CONCLUSIONS In BOS patients, greater longitudinal FEV₁ decline predicts increased mortality. Trends towards prolonged stabilization of FEV₁ and improved survival were observed with L-CsA-I receipt. Further analyses will aid in evaluating the utility of FEV₁ change as a survival predictor, having implications in BOS management and future trial design.

Figure 1

Flow diagram depicting study design.

Figure 2

Trajectories of forced expiratory volume in 1 second (FEV₁) for individual subjects, from transplantation to end of follow-up. FEV₁ trajectories are plotted in terms of% of personal maximum FEV₁ between lung transplantation and randomization.

Figure 3

Association between FEV₁% of personal post-transplant maximum and mortality risk – joint model analysis.