Do antifibrotics nintedanib (generic name: nintedanib) and pirfenidone (generic name: pirfenidone) change mortality in idiopathic pulmonary fibrosis (IPF)?

Do Antifibrotics Nintedanib and Pirfenidone Change Mortality in IPF?

Neither nintedanib nor pirfenidone have demonstrated a statistically significant reduction in mortality in randomized controlled trials, though pooled analyses and real-world data suggest a potential survival benefit. 1

Nintedanib and Mortality

Evidence from Pivotal Trials

• The INPULSIS-1 and INPULSIS-2 trials (1,066 patients total) showed no significant mortality benefit with nintedanib versus placebo (RR 0.70; 95% CI 0.44–1.11) over 52 weeks 1
• Pooled analysis of three nintedanib trials demonstrated a relative risk of 0.70 (95% CI 0.47–1.03) for mortality, which remained statistically non-significant despite moderate confidence in the estimate 1
• The INBUILD trial in progressive pulmonary fibrosis similarly did not show mortality differences, though it was not powered for this outcome 1

What Nintedanib Does Accomplish

• Slows FVC decline by approximately 125 ml/year compared to placebo (difference 125.2 ml; 95% CI 77.7–172.8) 1
• Reduces the proportion of patients experiencing ≥10% absolute FVC decline (RR 1.16; 95% CI 1.06–1.27) 1
• Shows a trend toward reducing acute exacerbations (HR 0.64; 95% CI 0.39–1.05), though not statistically significant 1

Pirfenidone and Mortality

Evidence from Clinical Trials

• The FDA label for pirfenidone explicitly states that all-cause mortality did not show a statistically significant difference in the pivotal Studies 1,2, and 3 2
• Pooled analyses from clinical trials suggest a 30% reduction in risk of disease progression (HR 0.70,95% CI 0.56–0.88), but this refers to FVC decline, not mortality 3

Real-World Mortality Data

• A 2024 meta-analysis of real-world studies found IPF-related mortality was 13.4% for pirfenidone and 7.2% for nintedanib, with all-cause mortality of 20.1% for pirfenidone and 16.6% for nintedanib 4
• These real-world mortality rates are higher than those observed in clinical trials, suggesting potential selection bias in trial populations 4
• Observational studies and pooled data analyses suggest antifibrotic therapies may improve life expectancy, though individual trials were not powered for mortality endpoints 5

Clinical Implications

What These Drugs Actually Do

• Both drugs slow disease progression by reducing the rate of FVC decline, which is the primary mechanism by which they may extend survival 1, 3, 6
• They reduce acute respiratory deteriorations, which are associated with very high morbidity and mortality 5
• The average life expectancy of untreated IPF patients is only 3-4 years, and FVC decline is almost linear regardless of baseline severity 5

Why Mortality Benefit Is Difficult to Demonstrate

• Individual trials have not been powered to show mortality reductions due to sample size and duration limitations 5
• The progressive, irreversible nature of IPF means that slowing FVC decline (which both drugs accomplish) is the most clinically meaningful outcome that can be measured in reasonable trial durations 1

Guideline Recommendations Despite Lack of Mortality Data

• The 2015 ATS/ERS/JRS/ALAT guidelines conditionally recommend both pirfenidone and nintedanib for IPF treatment based on their ability to slow disease progression 1
• The 2022 updated guidelines extend conditional recommendations for nintedanib to progressive pulmonary fibrosis beyond IPF 1

Important Caveats

Adverse Events Must Be Managed

• Nintedanib causes significant gastrointestinal adverse events: diarrhea (2.8x), nausea (3.1x), vomiting (3.6x), and weight loss (3.7x) compared to placebo 1
• Pirfenidone causes photosensitivity, fatigue, stomach discomfort, and anorexia 1
• Approximately 16% of patients discontinue either drug due to adverse events in real-world settings 4
• Dose reduction strategies are effective at managing side effects without compromising efficacy 5, 7

The Bottom Line for Clinical Practice

Prompt treatment with antifibrotics is critical because IPF progression is irreversible, and preserving lung function early is the only way these drugs can potentially extend survival, even though direct mortality benefit has not been proven in individual trials 5. The lack of statistically significant mortality benefit should not deter treatment, as slowing FVC decline and preventing acute exacerbations are the mechanisms by which these drugs likely improve outcomes 1, 5.