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Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias.

ABSTRACT: Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity. We used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event. Of 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine-Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81-0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86-0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65-0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78-0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations. The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

SUBMITTER: Hozumi H

PROVIDER: S-EPMC11293013 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias.

Hozumi Hironao H Miyashita Koichi K Nakatani Eiji E Inoue Yusuke Y Yasui Hideki H Suzuki Yuzo Y Karayama Masato M Furuhashi Kazuki K Enomoto Noriyuki N Fujisawa Tomoyuki T Inui Naoki N Suda Takafumi T

Respiratory research 20240731 1

<h4>Background and objective</h4>Pooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, w ...[more]

PMID: 39085869

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease that often causes disabling dyspnea. In IPF and other lung diseases, patient-reported outcomes (PROs)-questionnaires designed to gather information from the patient's perspective-can determine whether therapies affect dyspnea or other outcomes meaningful to patients. Before a PRO can be used confidently as an outcome measure in a longitudinal trial, studies must demonstrate the PRO's ability to capture change over time in the target population. Our goal in this study was to examine whether the UCSD Shortness of Breath Questionnaire does so in patients with IPF.MethodsWe used data from the Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis (STEP-IPF) to perform analyses that examined associations between UCSD scores and five external measures (anchors) at baseline and over time. Anchors included the Activity domain from St. George's Respiratory Questionnaire (SGRQ-A), the Physical Functioning domain from the SF-36 (SF36-PF), forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and distance walked during a timed walk test (6MWD). Linear regression models were used to examine relationships between UCSD scores and anchors over time.ResultsAt baseline, UCSD scores were weakly correlated with percent predicted FVC (-0.21, p = 0.005) and percent predicted DLCO (-0.20, p = 0.008), moderately correlated with 6MWD (-0.39, p < 0.0001) and strongly correlated with SGRQ-A (0.79, p < 0.0001) and SF36-PF (-0.72, p < 0.0001). Change over time in UCSD scores was associated with change in FVC (estimate = 2.54, standard error [SE] = 1.23, p = 0.04), SGRQ-A (estimate = 7.94, SE = 1.11, p < 0.0001), SF36-PF (estimate = 6.00, SE = 1.13, p < 0.0001), and 6MWD (estimate = 4.23, SE = 1.18, p = 0.0004) but not DLCO (estimate = 0.33, SE = 1.33, p = 0.80).ConclusionsThese results support the validity of the UCSD to assess change in dyspnea over time in patients with IPF.

Dataset Information

Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias.

Publications

Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias.

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