Impact of Lung Function Decline on Mortality in Lung Transplant Recipients: Long-Term Results From the L-CsA-i Study for the Prevention of Bronchiolitis Obliterans Syndrome

Frontiers in Medicine. 2022;9:897581
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Abstract

Background: Chronic lung allograft dysfunction (CLAD) is defined by a progressive loss of FEV1 and is associated with premature mortality. The aim of this study was to investigate the direct association between FEV1 decline and risk of mortality in patients after lung transplantation (LTx). Methods: 10-year follow up data from lung transplant recipients participating in randomized placebo-controlled clinical trial investigating the role of liposomal Cyclosporine A for inhalation (L-CsA-i) in the prevention of bronchiolitis obliterans syndrome (NCT01334892) was used. The association between the course of FEV1 over time and the risk of mortality was assessed using joint modeling and Cox regression analysis. Results: A total of 130 patients were included. Predictors of FEV1 decline were a higher absolute FEV1 at baseline and male sex. The joint model analysis indicated a significant association of change of FEV1 and risk of mortality (p < 0.001), with a predicted 3.4% increase in mortality risk for each 1% decline in FEV1. Significant predictors of a progressive phenotype were single LTx and treatment with placebo (as opposed to L-CsA-i). At the end of follow-up, 82 patients (63.1%) were still alive. Cox regression analyses for mortality identified only single LTx as a predictor of higher risk. Conclusion: Based on our observation of a close association between FEV1 and mortality over a period of 10 years we suggest FEV1 as a valid predictor of mortality and a suitable surrogate endpoint in the investigation of early interventions.

CET Conclusion

Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
This paper presents post hoc analyses from a previously published RCT. The original RCT investigated inhaled liposomal ciclosporin-A in the prevention of Bronchiolitis Obliterans Syndrome (BOS) after lung transplantation. 10-year follow up is now available for all 130 of the included patients. A strong association was found between baseline FEV1 and mortality risk and each 1% drop from baseline FEV1 was associated with 3.5% increased risk for mortality. The individual trajectories in lung function were highly variable between patients, however it seems that post-transplant FEV1 is a valid predictor of mortality and could be used to institute pre-emptive treatment.

Expert Review

Reviewer: Mr John O'Callaghan, Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences University of Oxford
Clinical Impact Rating : ☆☆☆☆☆ (0 of 5)
This paper presents some long term follow up from a previously published RCT of inhaled liposomal cyclosporine A in lung transplantation. The original study closed prior to reaching the target patient inclusion due to very slow accumulation of cases (Neurohr et al 2022). The paper by Kneidinger et al presents post hoc analyses from the RCT. The authors used the collected data to explore the relationship between decline in FEV1 and mortality in patients with single and double lung transplant. Whilst patients were included in the trial they had FEV1 measurements every 2 months, and for this analysis they were requested every 6 months up to ten years from inclusion. Complete data was retrieved for 91% of included patients, and reduced data for the remaining patients, censored at the last study visit. Mean follow up was 61 months. On average, FEV1 deteriorated over time but the trajectory for showed a great deal of diversity between patients. A highly significant correlation was found between the relative drop in FEV1 compared to baseline and mortality. In broad terms a 1% reduction in FEV1 compared to baseline, related to 3.4% higher mortality risk. In cox regression analysis, type of transplant was the only significant independent predictor of mortality; with recipients of single lung transplants having increased risk of progression. A significant amount of lung function must be lost before chronic lung allograft dysfunction can be diagnosed. Understanding the decline in FEV1 might allow early intervention and improvement in patient care through modification of the underlying process. Decline in FEV1 from baseline could also be used as a reliable surrogate outcome for mortality in clinical trials. References Neurohr, C. ; Kneidinger, N. ; Ghiani, A. ; et al. A randomized controlled trial of liposomal cyclosporine A for inhalation in the prevention of bronchiolitis obliterans syndrome following lung transplantation. American Journal of Transplantation. 2022;22(1):222-229

Study details

Aims : This study aimed to determine the association between forced expiratory volume in one second (FEV1) and risk of mortality in patients following lung transplantation, using the 10-year follow up data from the PARI Study No. 12011.201.
Interventions : Participants in the original trial were randomised to receive either liposomal Cyclosporine A inhalation (L-CsA-i) or placebo.
Participants : 130 lung transplant recipients.
Outcomes : The main outcomes of interest were the association between the course of post-transplant FEV1 over time and the risk of mortality, time to progression to allograft dysfunction and survival.
Follow up : 10 years

Metadata

Funding : Industry funding
Publication type : Randomised Controlled Trial
Trial registration : ClinicalTrials.gov - NCT01334892
Organ : Lung
Language : English
Author email : nikolaus.kneidinger@med.uni-muenchen.de
MeSH terms : lung transplantation