Antifibrotics in CPFE: What Long-Term Data Reveal

Combined pulmonary fibrosis and emphysema (CPFE) is characterized by fibrosis predominantly in the lower lung zones and emphysema in the upper zones. Although antifibrotic therapies such as pirfenidone and nintedanib have demonstrated efficacy in idiopathic pulmonary fibrosis (IPF), their effects in CPFE remain uncertain because these patients were generally excluded from pivotal antifibrotic trials due to FEV₁/FVC ratio cut-offs.

Examining Antifibrotics in a Nationwide Cohort

Researchers addressed this question using the Korean IPF Cohort, a multicenter registry spanning 25 hospitals. CPFE was defined as IPF with emphysema involving more than 5% of lung volume on initial computed tomography. Among 3,111 registry participants, 966 patients with CPFE were identified.

Because this was a retrospective, nonrandomized study, the investigators used several approaches to reduce potential bias. A 6-month landmark analysis excluded patients who died, underwent lung transplantation, or were lost to follow-up during that period. Propensity scores based on age, sex, body mass index, lung cancer history, and Composite Physiologic Index were then used to create 292 matched pairs of patients receiving or not receiving antifibrotic therapy.

Survival and Lung Function Tell Different Stories

After matching, conventional Cox analysis suggested a higher risk of death or lung transplantation among antifibrotic-treated patients (HR=1.29; p=0.045). However, the survival curves crossed at approximately 100 months, violating the proportional hazards assumption underlying that analysis. The investigators therefore used restricted mean survival time (RMST), which estimates average survival over a specified period without assuming that relative hazards remain constant over time.

Across 100 months, mean transplant-free survival was 66.26 months without antifibrotics and 59.39 months with treatment, a difference of −6.87 months that was not statistically significant (p=0.264). Thus, the adjusted analysis did not demonstrate an overall survival benefit with antifibrotic therapy.

A different pattern emerged for lung function. Among 310 treated patients with longitudinal pulmonary function data, piecewise linear mixed models compared trajectories for up to 3 years before and after treatment initiation. The annual decline in DL_CO percent predicted slowed from −4.19% before treatment to −2.97% afterward. Absolute DL_CO decline similarly slowed from −0.83 to −0.69 mL/mmHg/min per year. FVC percent predicted declined somewhat more slowly after treatment, from −2.45% vs −2.14% per year, whereas absolute FVC decline remained similar.

A Physiologic Signal, but Not Yet a Survival Benefit

These findings suggest that antifibrotic therapy may attenuate physiologic decline in CPFE, particularly deterioration in gas-transfer capacity, even though a statistically significant survival advantage was not demonstrated. Importantly, the observational design leaves room for residual confounding despite landmark analysis and propensity matching. Pulmonary hypertension could not be adequately incorporated into survival analyses, and DL_CO itself can vary with pulmonary vascular disease, hemoglobin levels, and measurement conditions.

Rather than positioning DL_CO as a standalone marker, the authors propose incorporating serial DL_CO alongside imaging, exercise tolerance, and clinical symptoms when assessing CPFE progression and treatment response. Prospective randomized studies will be needed to determine whether the observed preservation of lung physiology ultimately translates into improved long-term clinical outcomes.

Reference:

Gwon HR, Lee J, Chung MP, et al. The Efficacy of Antifibrotics in Combined Pulmonary Fibrosis and Emphysema: A Nationwide Multicentre Retrospective Cohort Study. Arch Bronconeumol. Published online September 18, 2026. doi:10.1016/j.arbres.2026.08.001