Effectiveness of Cystic Fibrosis Transmembrane Conductance Regulator Modulator Therapy on Risk of Death for Individuals With Cystic Fibrosis

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BACKGROUND: To date, clinical trials of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies have focused on outcomes that can be captured in relatively short follow-up periods. The effectiveness of CFTR modulator therapies on survival has not been described fully. RESEARCH QUESTION: What is the population-level treatment effect of initiating any CFTR modulator therapy compared with no initiation on the risk of death in people with cystic fibrosis (CF)? STUDY DESIGN AND METHODS: We conducted a retrospective cohort study using United States Cystic Fibrosis Foundation Patient Registry data from between 2012 and 2022. We included individuals who met eligibility criteria for a CFTR modulator prescription (based on age and genotype of 2020 regulatory approvals and no prior use). At every clinic or telehealth visit, we assessed eligibility and classified treatment status based on registry records. We included individuals in the analysis multiple times if eligibility was met at multiple visits. We followed individuals from each visit until death (outcome), lung transplantation, loss to follow-up, or administrative censoring. We censored untreated observations if they later initiated CFTR modulator therapy. We estimated 8-year risk curves using Kaplan-Meier and hazard ratios (HRs) from Cox regression models. We used inverse probability weighting to balance baseline covariates and to account for nonrandom censoring. RESULTS: We included 25,103 individuals and 178,835 visits; 18,056 individuals initiated therapy. The 8-year risk difference of death resulting from initiating CFTR modulator therapy was -7.2% (95% CI, -9.6 to -4.9). The hazard for death was 66% lower after CFTR modulator initiation than without use (HR, 0.34; 95% CI, 0.28 to 0.41). INTERPRETATION: Our results show that CFTR modulator therapies reduce the risk of death among people living with CF over 8 years. This improved understanding will allow individuals living with CF and clinical providers to have reasonable expectations about survival and to allocate care and resources aligned with increased life expectancy appropriately.

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