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Overview of Idiopathic Pulmonary Fibrosis, Evidence-Based Guidelines, and Recent Developments in the Treatment Landscape
Marilyn K. Glassberg, MD
Participating Faculty

Overview of Idiopathic Pulmonary Fibrosis, Evidence-Based Guidelines, and Recent Developments in the Treatment Landscape

Marilyn K. Glassberg, MD
Although diagnostic recommendations were updated in 2018,8 the 2015 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Association (ATS/ERS/JRS/ALAT) international IPF therapy guidelines remain a primary resource for the pharmacologic management of the disease.34 In 2018, the JRS published updated clinical guidelines for the treatment of IPF.35 Table 1 provides a summary of recommendations from the 2015 ATS/ERS/JRS/ALAT and 2018 JRS guidelines, along with strength of recommendation and confidence-in-effect estimates.34,35 The 2 most recent guidelines agree on recommendations, with the exception of some therapeutic approaches addressed by 1 publication and not the other. The only therapies currently supported by guideline recommendations are nintedanib, pirfenidone, and antireflux medications.34,35 When selecting between the antifibrotic agents, clinicians should consider patient preference, tolerance, potential AEs, drug interactions, and comorbid conditions.


Nintedanib, an antifibrotic agent approved for the treatment of IPF, is an intracellular inhibitor that targets multiple tyrosine kinase receptors that have been shown to be involved in lung fibrosis, including the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors.36,37 The prescribing information for nintedanib is shown in Table 2.38 Several warnings and precautions should be noted with the use of nintedanib, including the potential of drug-induced liver injury, embryo–fetal toxicity, bleeding and arterial thromboembolic events, and gastrointestinal (GI) perforation.38 The most common AEs associated with nintedanib use include diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight loss, and hypertension. Notably, smoking can decrease the patient’s exposure to nintedanib, which may reduce its efficacy profile.38

The approval of nintedanib in patients with IPF and subsequent guideline recommendations for its use are primarily based on outcomes from the INPULSIS-1 and INPULSIS-2 trials, which are summarized in Table 3.37 The data from the INPULSIS trials demonstrated the efficacy of nintedanib in slowing the annual rate of decline of FVC as compared with placebo. Patients (95%) receiving nintedanib experienced at least 1 AE during the two phase 3 trials, 62% experienced diarrhea, and 30% experienced at least 1 serious AE.39 In post hoc analyses, nintedanib has been shown to significantly reduce the risks of a first acute exacerbation reported as a serious AE (HR, 0.57; 95% CI, 0.32-0.99; P = .0476) and a first confirmed/suspected acute exacerbation reported as a serious AE (HR, 0.30; 95% CI, 0.14-0.64; P = .0019).40

Real-world expectations involving shared decision making necessitates that pharmacists explain to patients the AEs associated with nintedanib use. Recently published data from the long-term follow-up, open-label extension study to the INPULSIS trials, INPULSIS-ON, showed a similar safety profile that was demonstrated in phase 3 trials over a median exposure time of 44.7 months (range, 11.9-68.3 months).39 Fifteen percent of patients discontinued nintedanib permanently due to diarrhea, which was the most frequent AE (60.1%-71.2%). Other AEs including bronchitis, nasopharyngitis, cough, nausea, and upper respiratory tract infection occurred in fewer than 30% of study participants. Among patients who received nintedanib in each of the INPULSIS-1, INPULSIS-2, and INPULSIS-ON trials, the event rate per 100 patient exposure-years of bleeding was 8.4, which may be related to the known vascular endothelial growth factor antagonism of nintedanib.38 Cardiac events included major cardiovascular AEs (3.6/100) and myocardial infarction (1.3/100), underscoring the recognition of cardiac comorbidities in patients with IPF.39

Pooled results from 5 clinical trials, including the INPULSIS and INPULSIS-ON trials, found no new safety signals in 1126 patients in the pooled nintedanib group compared with the 565 patients in the pooled placebo group.41 Diarrhea occurred at a lower rate in the pooled nintedanib group than those observed during the INPULSIS trials (76.5 vs 112.6 events per 100 patient exposure-years), and diarrhea was generally well managed for most patients. Median survival was 11.6 (95% CI, 9.6-14.1) and 3.7 (95% CI, 2.5-5.4) years in the pooled nintedanib and placebo groups, respectively.41

Given the high rates of AEs associated with nintedanib use in clinical trials, data from real-world observational studies should also be considered. An observational study in Greece found that the most common AE associated with nintedanib use was diarrhea, which occurred in 55.3% of participants. Of 94 patients with IPF, 20 (21.2%) permanently discontinued nintedanib due to serious AEs.42 In another study, 50.0% and 45.4% of 108 patients with IPF experienced diarrhea and anorexia, respectively, during the course of nintedanib therapy, with 97.2% of patients experiencing at least 1 AE and 53.3% discontinuing therapy as the result of an AE.43 Pharmacists can assist in managing GI complications related to nintedanib use by recommending hydration and use of the recommended over-the-counter antidiarrheals such as loperamide, and/or referring to their physician for potential dose reduction.


Pirfenidone is an orally bioavailable antifibrotic agent approved for the treatment of IPF.44,45 Although its exact mechanism of action is unknown, animal models of lung fibrosis have shown that pirfenidone regulates the activity of transforming growth factor β and tumor necrosis factor α, inhibits fibroblast proliferation and collagen synthesis, and reduces cellular and histologic markers of fibrosis.45 Prescribing information for pirfenidone is shown in Table 4.46 AEs include GI symptoms, photosensitivity, skin rash, anorexia, and liver toxicity; these effects were generally well tolerated during clinical trials, especially with dose reduction.3 As with nintedanib, active smokers will experience a reduced exposure of pirfenidone, which may alter the efficacy of the agent in IPF treatment.46

The translation of clinical trial data to practice is a necessary component of effective IPF management. Results from the pivotal phase 3 CAPACITY and ASCEND trials are shown in Table 5.45,47 According to outcomes data from the phase 3 CAPACITY and ASCEND trials, 2403 mg/day of pirfenidone significantly reduced the decline in FVC, improved progression-free survival time, and increased the 6MWT distance compared with placebo among patients with IPF.45,47 The most common AEs in the CAPACITY trial among patients who received pirfenidone versus placebo were nausea (36% vs 17%), rash (32% vs 12%), dyspepsia (19% vs 7%), dizziness (18% vs 10%), and vomiting (14% vs 4%).45 Patients taking pirfenidone in the ASCEND trial experienced more AEs compared with those taking placebo, with the most common being nausea (36% vs 13.4%) and rash (28.1% vs 8.7%); AEs led to study discontinuation in 14.4% and 10.8% of patients taking pirfenidone and placebo, respectively.47

A post hoc analysis of 1247 patients from the CAPACITY and ASCEND trials found a lower risk of respiratory-related hospitalizations with pirfenidone treatment compared with placebo (HR, 0.52; 95% CI, 0.36-0.77; P = .001); however, all-cause and nonrespiratory-related hospitalizations were not affected by pirfenidone use. Furthermore, the protective effect of pirfenidone on respiratory-related hospitalizations lost significance after 52 weeks, leaving long-term conclusions uncertain.48 Another post hoc analysis of the CAPACITY and ASCEND trials found that pirfenidone was associated with significantly fewer progression events compared with placebo (17.0% vs 30.1%; P <.0001); additionally, death following a progression event occurred less frequently with pirfenidone than placebo (2.1% vs 6.3%; P = .0002).44 A recent post hoc analysis of the open-label, long-term extension study, RECAP (NCT00662038) found that longer-term pirfenidone treatment resulted in a similar rate of lung function decline and AEs in patients with more advanced versus less advanced IPF, indicating that pirfenidone is safe, efficacious, and well tolerated in patients with IPF regardless of advanced disease.49

Alongside clinical trials, observational and retrospective analyses of pirfenidone in IPF must also be considered, as these studies provide real-world expectations for treatment outcomes. During a real-world, long-term follow-up study of 841 patients with IPF, fewer than one-fourth of those who received pirfenidone experienced disease progression (ie, decline of ≥10% FVC and ≥15% diffusing capacity of the lungs for carbon monoxide [DLCO]) by 2 years of follow-up. At 5 years of follow-up, pirfenidone had significantly increased survival compared with no antifibrotic therapy (55.9% vs 31.5%; P = .002).50 A French ancillary study of the 2-year observational PASSPORT trial reported a mean absolute change in percent predicted FVC to be –2.4% and –3.8% and in 6MWT to be 8.6 and 3.1 meters at 12 and 24 months, respectively. The median duration of pirfenidone use was 16.3 months, with a median progression-free survival of 18.4 months. Acute exacerbation and PH occurred in 20.0% and 8.4%, respectively, of patients who received pirfenidone. Reasons for early discontinuation of pirfenidone included AEs (31.3%), death (11.5%), and disease progression (10.9%).51 Hanta et al also evaluated outcomes in the real-world use of pirfenidone in patients with IPF. After 6 months of treatment, 58.3% of patients experienced less cough, and 55% of patients experienced at least

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