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. 2024 Jul 31;25(1):293.
doi: 10.1186/s12931-024-02922-y.

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

Hironao Hozumi  1 , Koichi Miyashita  2 , Eiji Nakatani  3 , Yusuke Inoue  2 , Hideki Yasui  2 , Yuzo Suzuki  2 , Masato Karayama  2 , Kazuki Furuhashi  2 , Noriyuki Enomoto  2 , Tomoyuki Fujisawa  2 , Naoki Inui  2   4 , Takafumi Suda  2
Affiliations

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

Hironao Hozumi et al. Respir Res. .

Abstract

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusions: The results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

Keywords: Antifibrotics; Idiopathic pulmonary fibrosis; Mortality; Nintedanib; Pirfenidone.

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Conflict of interest statement

Hozumi received honoraria for speaking engagements from Boehringer Ingelheim, which is not related to this manuscript. Suda received honoraria for speaking engagements from Boehringer Ingelheim and SHIONOGI & CO., LTD., but none of them are related to this manuscript. Miyashita, Nakatani, Inoue, Yasui, Suzuki, Karayama, Furuhashi, Enomoto, Fujisawa and Inui declare that no competing interests exist.

Figures

Fig. 1
Fig. 1
Flow diagram presenting the processes used for enrolling patients, grouping for target trial emulation, and propensity score matching. (A) Flow diagram of patient enrollment. (B) Flow diagram of grouping patients with idiopathic pulmonary fibrosis for target trial emulation with a new-user design for antifibrotics. Patients who had not used antifibrotics between the date of idiopathic pulmonary fibrosis (IPF) diagnosis and the date of censoring or death were categorized as unexposed patients, whereas those who started using antifibrotics on the date of IPF diagnosis were categorized as antifibrotic-exposed patients. The intention-to-treat analysis included the unexposed patients and all patients who were assigned to first-line antifibrotic treatment (nintedanib or pirfenidone). Multivariate Fine–Gray models were used in the intention-to-treat analyses of the effects of antifibrotics on mortality. (C) Flow diagram of propensity score matching. In the target trial emulation, propensity score-matched comparisons were made between antifibrotic-exposed and unexposed patients. Propensity scores were calculated using a logistic regression model adjusted for age, sex, cerebrovascular disease, dementia, acquired immunodeficiency syndrome/human immunodeficiency virus, myocardial infarction, renal disease, congestive heart failure, peripheral vascular disease, chronic pulmonary disease, peptic ulcer, liver disease, diabetes mellitus, hemiplegia or paraplegia, venous thromboembolic disease, pulmonary hypertension, long-term oxygen use, and corticosteroid use at baseline
Fig. 2
Fig. 2
Forest plots of a subgroup intention-to-treat analysis of the effects of nintedanib and pirfenidone on mortality. Full versions of these figures are shown in Additional file: Figures S5 and S6. HR, hazard ratio; CI, confidence interval
Fig. 3
Fig. 3
Intention-to-treat survival curves of propensity score-matched idiopathic pulmonary fibrosis patients who were or were not treated with antifibrotics. (A) The nintedanib-exposed group had a significantly higher survival rate than the unexposed group (HR, 0.74; 95% CI, 0.68–0.80; p < 0.0001). The median survival times of the nintedanib-exposed and unexposed groups were 38.7 and 34.6 months, respectively. (B) The pirfenidone-exposed group had a significantly higher survival rate than the unexposed group (HR, 0.86; 95% CI, 0.81–0.92; p < 0.0001). The median survival times of the pirfenidone-exposed and unexposed groups were 34.7 and 31.6 months, respectively. HR, hazard ratio; CI, confidence interval
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