Table 2. Main studies evaluating the impact of antifibrotics on idiopathic pulmonary fibrosis regarding mortality and acute exacerbation of idiopathic pulmonary fibrosis.

Study	Study Type	Year	Antifibrotic	Outcome	Main Findings	Mortality Reduction	Effect on Acute Exacerbation
SHIONOGI Phase 2 - Research Group for Diffuse Lung Diseases Azuma et al. 17	Randomized phase II trial	2005	Pirfenidone	Lowest oxygen saturation during 6MWT	Negative for the primary endpoint, but pirfenidone significantly reduced the decline in vital capacity at 9 months and reduced the incidence of acute exacerbations when compared with placebo.	No	Yes
SHIONOGI Phase 3 - Pirfenidone Clinical Study Group Taniguchi et al. 16	Randomized trial	2010	Pirfenidone	FVC decline	Pirfenidone reduced the decline of lung function and improved progression-free survival.	No	No
CAPACITY-004 and CAPACITY-006 Noble et al. 22	Randomized trial	2011	Pirfenidone	FVC decline	Pirfenidone reduced the rate of decline in FVC at 72 weeks in CAPACITY-004 (but not in CAPACITY-006) and reduced the mean change from baseline in 6MWD and improved progression-free survival in the pooled analysis.	No	N/A
TOMORROW Richeldi et al. 19	Randomized phase II trial	2011	Nintedanib	FVC decline	Nintedanib reduced annual decline in FVC, incidence of acute exacerbations, and SGRQ score (improved quality of life)	No	Yes
INPULSIS-1 and INPULSIS-2 Richeldi et al. 23	Randomized trial	2014	Nintedanib	FVC decline	Nintedanib reduced the annual rate of decline in FVC by 51% (p < 0.001)	No	Yesa
ASCEND King Jr. et al. 20	Randomized trial	2014	Pirfenidone	FVC decline	Pirfenidone reduced change in FVC from baseline and improved progression-free survival (defined as death, decrease in FVC, or decrease in 6MWD).	No	N/A
Washington Group Canestaro et al. 33	Systematic Review and Meta-analysis	2016	Pirfenidone + Nintedanib	All-cause and respiratory-specific death	Negative for primary endpoint, but pirfenidone and nintedanib had effects approaching significance under a fixed-effects model for all-cause mortality.	No	N/A
Combined CAPACITY and ASCEND trials Noble et al. 34	Pooled analysis	2016	Pirfenidone	FVC decline or death	Pirfenidone reduced decline in lung function and improved other measures such as progression-free survival, 6MWD, and dyspnea.	Yes	N/A
Combined TOMORROW and INPULSIS Richeldi et al. 23	Pooled analysis	2016	Nintedanib	FVC decline, acute exacerbation, SGRQ, and mortality in 52 weeks	Nintedanib reduced FVC decline, time to first acute exacerbation and on-treatment (but not all-cause) mortality	No	Yes
RECAP Costabel et al. 35	Open-label extension study	2016	Pirfenidone	Long-term safety	Pirfenidone was deemed to be safe. Sustained effect on FVC decline and a median on-treatment survival of 77.2 months was observed.	N/A	N/A
Combined SHIONOGI, CAPACITY and ASCEND trials Nathan et al. 21	Pooled analysis	2017	Pirfenidone	Long-term mortality (120 weeks)	Pirfenidone was associated with a reduced relative risk of death for patients for all mortality outcomes (all-cause mortality, treatment-emergent all-cause mortality, idiopathic-pulmonary-fibrosis-related mortality, and treatment-emergent idiopathic-pulmonary-fibrosis-related mortality).	Yes	N/A
AIPFR Jo et al. 27	Real-life Registry from Australia	2017	Pirfenidone + Nintedanib	Baseline characteristics	Improved survival in patients taking antifibrotics even after multivariate analysis adjusted for age, gender, smoking, BMI, and baseline lung function.	Yes	N/A
INSTAGE Kolb et al. 36	Randomized trial	2018	Nintedanib + sildenafil	Change in SGRQ	Addition of sildenafil to nintedanib did not improve dyspnea and similar percentages of patients had at least one acute exacerbation or died.	No	No
Post-hoc CAPACITY and ASCEND trials Nathan et al. 37	Pooled data analysis	2018	Pirfenidone	Continued effect of pirfenidone after a disease progression event	Patients receiving pirfenidone who experienced an initial absolute or relative decline in percent predicted FVC were less likely to experience further decline in lung function or death in the subsequent 6 months compared with those receiving placebo.	Yes	Yesb
INPULSIS-ON Crestani et al. 24	Open-label extension study	2018	Nintedanib	Safety and long-term efficacy	Nintedanib had a safety profile consistent with that observed in the INPULSIS trials and effect on slowing progression persisted beyond 4 years.	N/A	N/A
Post-hoc TOMORROW, INPULSIS, INPULSIS-ON and Phase IIIb trial Lancaster et al. 38	Pooled data analysis	2019	Nintedanib	Safety and survival	Treatment with nintedanib was considered safe. Survival was estimated as 11.6 years in the treated group (versus 3.7 in the placebo group).	Yes	N/A
EMPIRE Zurkova et al. 39	Real-life registry from Czech Republic	2019	Pirfenidone	Overall survival and FVC decline	Pirfenidone increased overall 5-year survival versus no-antifibrotics (55.9% vs. 31.5% alive, respectively, p = 0.002).	Yes	No
FinnishIPF Kaunisto et al. 28	Real-life registry from Finland	2019	Pirfenidone + Nintedanib	Demographics and survival	Patients who received ≥ 6 months of treatment had better survival compared with those who did not receive treatment in the unadjusted analysis.	Yes	N/A
Insurance Database Dempsey et al. 25	Retrospective cohort	2019	Pirfenidone + Nintedanib	Mortality and hospitalization	Lower risk of all-cause mortality and hospitalization compared with no treatment.	Yes	Yesb
IPF-PRO Snyder et al. 40	Real-life registry	2019	Pirfenidone + Nintedanib	Predictors of death or lung transplant	The authors were unable to evaluate associations between the use of antifibrotic therapy at enrollment and death or lung transplant.	N/A	N/A
INSIGHTS-IPF Registry Behr et al. 30	Real-life registry in Germany	2020	Pirfenidone + Nintedanib	Survival and FVC decline	Survival was significantly higher in IPF patients on antifibrotic therapy, but the course of lung function parameters was similar in patients on antifibrotic therapy or not.	Yes	N/A
Korean Cohort Kang et al. 26	Retrospective cohort	2020	Pirfenidone + Nintedanib	Mortality, hospitalization, and acute exacerbation	Antifibrotic treatment significantly reduced the risks of mortality [hazard ratio (HR) = 0.59], all-cause hospitalization (HR = 0.71), respiratory-related hospitalization (HR = 0.67), acute exacerbation (HR = 0.69), and mortality after acute exacerbation (HR = 0.60).	Yes	Yes
Petnak et al. 31	Systematic review and meta-analysis	2021	Pirfenidone + Nintedanib	Mortality and acute exacerbations	Antifibrotic treatment appears to reduce the risk of all-cause mortality and acute exacerbations.	Yes	Yes
REFIPI Caro et al. 41	Real-life registry	2022	Pirfenidone + Nintedanib	Demographic, clinical, serological, functional, tomographic, histological, and treatment variables	Most patients in the REFIPI received antifibrotics, which were well tolerated and associated with a lower rate of adverse events than that reported in clinical trials.	N/A	N/A

IPF: idiopathic pulmonary fibrosis; AE-IPF: acute exacerbation of IPF; 6MWT: six-minute walking test; SGRQ: Saint-George’s Respiratory Questionnaire; and 6MWD: six-minute walk distance. ^aOnly INPULSIS-1 showed a reduction in the incidence of AE-IPF. ^bRespiratory-related hospitalization was analyzed as a surrogate for AE-IPF.