Long-term impact of ivacaftor on mortality rate and health outcomes in people with cystic fibrosis

Abstract

Background: Ivacaftor (IVA) has been shown to improve lung function and other clinical outcomes in people with cystic fibrosis (CF). A decade of real-world IVA availability has enabled the examination of long-term outcomes with this treatment. This retrospective, longitudinal cohort study investigated the impact of IVA on mortality rate and health outcomes among people with CF in the US.

Methods: Data from the US CF Foundation Patient Registry from January 2010 to December 2019 were analysed. The IVA-treated cohort included people with a CF transmembrane conductance regulator (CFTR) gating mutation (excluding R117H); age-matched comparator cohort included people with a F508del and a minimal function CFTR mutation who had no prior CFTR modulator treatment. Baseline characteristics were balanced between cohorts using standardised mortality ratio weighting generated from propensity scores. Outcomes of interest were overall survival, lung transplant, percent predicted forced expiratory volume in 1 s (ppFEV₁), body mass index (BMI), pulmonary exacerbations (PEx), outpatient visits and hospitalisations.

Findings: Over a maximum follow-up of 7.9 years, the IVA-treated cohort (N=736) had lower rates of mortality (hazard ratio [HR] (95% CI): 0.22 (0.09 to 0.45)), lung transplant (HR: 0.11 (95% CI 0.02 to 0.28)), PEx (rate ratio: 0.49 (95% CI 0.42 to 0.55)) and all-cause hospitalisations (rate ratio: 0.50 (95% CI 0.43 to 0.56)) as well as better lung function (mean difference in ppFEV₁: 8.46 (95% CI 7.34 to 9.75)) and higher BMI/BMI z-scores (mean difference 1.20 (95% CI 0.92 to 1.71) kg/m² and 0.27 (95% CI 0.25 to 0.40), respectively) than the comparator cohort (N=733).

Interpretation: Our analysis suggests that IVA provides sustained clinical benefits in people with CF over a follow-up period of approximately 8 years. These findings reinforce the existing real-world evidence that IVA can slow disease progression and decrease the healthcare burden of CF over the long term.

Keywords: Cystic Fibrosis.

Figure 1. SMR-weighted Kaplan-Meier analysis and HRs for overall survival. Covariates included in the propensity score used to generate SMR weights were sex, race, ethnicity, type of health insurance, employment status, median household income by zip code (categorical), education level, average of best available ppFEV₁ in each quarter (categorical), change in ppFEV₁ (categorical), number of PEx, average BMI/BMI z-scores (categorical), prevalence of CF-related complications, prevalence of respiratory micro-organisms, number of hospitalisations and outpatient visits, and medication use. †People without the event were censored at their end of data availability, which was imputed as 31 December of the last year that the individual had annual data available. The mean SMR-weighted follow-up duration was 6.5 years in the IVA-treated cohort and 6.3 years in the comparator cohort. ‡Visual inspection of Schoenfeld residuals was performed to assess the proportional hazards assumption for IVA treatment. As the proportional hazards assumption was violated, a treatment-by-time interaction term was included in the model to account for time-dependent effects. §95% CI does not include the null. BMI, body mass index; CI: confidence interval; HR: hazard ratio; IVA, ivacaftor; PEx, pulmonary exacerbation; ppFEV₁, per cent predicted forced expiratory volume in 1 s; OS, overall survival; ref: reference; SMR, standardised mortality ratio.

Figure 2. SMR-weighted Kaplan-Meier analysis and HRs for lung transplant. Covariates included in the propensity score used to generate SMR weights were sex, race, ethnicity, type of health insurance, employment status, median household income by zip code (categorical), education level, average of best available ppFEV₁ in each quarter (categorical), change in ppFEV₁ (categorical), number of PEx, average BMI/BMI z-scores (categorical), prevalence of CF-related complications, prevalence of respiratory microorganisms, number of hospitalisations and outpatient visits, and medication use. †People without the event were censored at the first occurrence of treatment with a CFTRm therapy other than IVA, death, pregnancy or end of data availability. As only annual pregnancy and lung transplant data were available, the date of pregnancy and lung transplant were imputed as 1 January. The end of data availability was imputed as 31 December of the last year that the individual had annual data available. People in the IVA-treated cohort were also censored at time of IVA discontinuation. Patients in the comparator cohort were also censored at the time of first occurrence of treatment with IVA. The mean SMR-weighted follow-up duration was 5.6 years for the IVA-treated cohort and 6.0 years for the comparator cohort. ‡Visual inspection of Schoenfeld residuals was performed to assess the proportional hazards assumption for IVA treatment. As the proportional hazards assumption was violated, a treatment-by-time interaction term was included in the model to account for time-dependent effects. §95% CI does not include the null. BMI, body mass index; CI: confidence interval; CF, cystic fibrosis; CFTRm, cystic fibrosis transmembrane conductance regulator modulator; HR: hazard ratio; IVA, ivacaftor; PEx, pulmonary exacerbation; ppFEV₁, per cent predicted forced expiratory volume in 1 s; ref: reference; SMR, standardised mortality ratio.

Figure 3. SMR-weighted mean ppFEV₁ over time. **,†, ‡ For data missing over a 6-month period in the follow-up period, the value of the last observation was carried forward (ie, the individual’s value from the previous 6-month period was used in place of the missing observations). †People were censored at the first occurrence of treatment with a CFTRm therapy other than IVA, death, pregnancy, lung transplant or end of data availability. As only annual pregnancy and lung transplant data were available, the date of pregnancy and lung transplant were imputed as 1 January. The end of data availability was imputed as 31 December of the last year that the individual had annual data available. People in the IVA-treated cohort were also censored at time of IVA discontinuation. People in the comparator cohort were also censored at time of first occurrence of treatment with IVA. ‡Covariates included in the propensity score used to generate SMR weights were sex, race, ethnicity, type of health insurance, employment status, median household income by zip code (categorical), education level, average of best available ppFEV₁ in each quarter (categorical), change in ppFEV₁ (categorical), number of PEx, average BMI/BMI z-scores (categorical), prevalence of CF-related complications, prevalence of respiratory micro-organisms, number of hospitalisations and outpatient visits, and medication use. Due to extreme propensity scores, trimming weights at the first and the 99th percentile was used to reduce the contribution of individuals with large weights, as they were unlikely to be representative of the overall study cohorts. §Matched groups with all individuals having ≥1 ppFEV₁ measurement between the index date and the end of 12, 24, 36, 48 or 60 months were included in the analysis for the corresponding time period. Matched groups were dropped if they included ≥1 individual with no outcome measurements available during the observation period. **The mean ppFEV₁ and mean differences were estimated using generalising estimating equation models with normal distribution and autoregressive covariance structure while adjusting for follow-up time. Interaction terms between IVA and time variables were also included in the model. SMR weights for the IVA-treated and comparator cohorts were incorporated in calculating the intercept and slope estimates in the model. This resulted in a small difference in the unadjusted and SMR-weighted mean ppFEV₁ values for the IVA cohort. ††95% CI does not include the null. BMI, body mass index; CFTRm, cystic fibrosis transmembrane conductance regulator modulator; IVA, ivacaftor; PEx, pulmonary exacerbation; ppFEV₁, per cent predicted forced expiratory volume in 1 s; SMR, standardised mortality ratio.

Figure 4. SMR-weighted IRRs for comparison of hospitalisations, outpatient visits and PEx. *The mean (min–max) SMR-weighted follow-up duration was 5.7 (0.1–7.9) years in the IVA-treated cohort and 6.2 (0.0–7.9) years in the comparator cohort. †Pulmonary-related hospitalisations included PEx-related hospitalisations and hospitalisations related to pulmonary complications. ‡The mean (min–max) SMR-weighted follow-up duration was 5.6 (0.1–7.9) years in the IVA-treated cohort and 6.0 (0.0–7.9) years in the comparator cohort. §PEx included episodes requiring home IV antibiotics or PEx-related hospitalisations. GI, gastrointestinal; HCRU: healthcare resource utilization; IV: intravenous; IVA, ivacaftor; PEx, pulmonary exacerbation; ref, reference; SMR, standardised mortality ratio.