Real-world association between ivacaftor initiation and lung function variability: A registry study

Background: 

Increased variability in forced expiratory volume in 1 s of % predicted (FEV₁pp) has been associated with accelerated lung function decline in individuals with cystic fibrosis (CF). Lung function variability is a leading predictor of decline, but the association between ivacaftor initiation and FEV₁pp variability has not been characterized. 

Methods: 

We utilized the Cystic Fibrosis Foundation Patient Registry (2008–2020) to quantify this association and identify risk factors of increased variability. Linear mixed effects models were used to compare pre- and post-ivacaftor initiation periods for established outcome measures of FEV₁pp variability: i) maximum and ii) median deviations from the best (highest) FEV₁pp during each period; iii) maximum, iv) median, and v) standard deviation about the trendline of the FEV₁pp trajectory in each period. 

Results: 

The analysis cohort included 527 individuals. Across outcomes, FEV₁pp variability was reduced after ivacaftor initiation (median reduction: 1.85 % predicted). Reductions were robust with highest magnitudes of effect identified using maximum deviation from the best FEV₁pp while most consistent findings were reached with trendline measures, particularly median deviation. Risk factors for increased FEV₁pp variability differed between children and adults but were consistent between G551D and R117H subgroups. F508del homozygous patients followed contemporaneously exhibited minimal change in variability (median change: 0.25 % predicted). Reduced variability weakly correlated with changes in FEV₁pp and slope, but higher levels of pre-ivacaftor variability were associated with greater reductions. 

Conclusions: 

There was evidence that ivacaftor initiation reduces FEV₁pp variability in people with CF. Quantifying FEV₁pp variability may have utility as a marker of therapeutic effectiveness.