Abstract
Background/Aim
Nintedanib, an antifibrotic drug, is expected to slow the progression of interstitial lung diseases (ILDs). This study aimed to evaluate the usefulness of nintedanib for patients with idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF) who would otherwise be excluded due to being unable to undergo invasive tests.
Patients and Methods
We retrospectively reviewed the medical records of all IPF and PPF patients who received nintedanib at our hospitals. This study included 187 patients whose severity could be assessed using the Japanese Respiratory Society classification, which allows for non-invasive severity evaluation, rather than the Gender-Age-Physiology score. Patients were classified into three groups based on their nintedanib administration status: a continuation group, a dose reduction group, and a discontinuation group.
Results
There were no significant differences in patient characteristics among the three groups. The duration of nintedanib administration in the discontinuation group was shorter than in the continuation and dose reduction groups. There was a significant difference in survival time from the start of nintedanib administration, with a shorter survival time in the discontinuation group. In addition, the incidence of acute exacerbations was lower in the continuation and the dose reduction groups than in the discontinuation group. Developing an acute exacerbation and discontinuation of nintedanib administration were identified as poor prognostic factors.
Conclusion
Even in patients with ILD who would be excluded due to selection bias, continuing nintedanib might show positive effects on survival. The results obtained in this study are considered worthy of further verification.
Keywords: Interstitial lung disease, idiopathic pulmonary fibrosis, progressive pulmonary fibrosis, nintedanib, JRS severity staging, survival
Introduction
Idiopathic pulmonary fibrosis (IPF) is the most common type of interstitial lung disease (ILD) and is a progressive, intractable disease of unknown etiology (1) The most recent definition of IPF was provided in 2022 in the international guidelines from the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) (1). Progressive pulmonary fibrosis (PPF) refers to a group of ILDs in which progressive fibrosis is observed during the clinical course (1). PPF is a diverse group of diseases, including autoimmune ILD, idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs (2). The INBUILD trial, an international Phase III clinical trial of the antifibrotic drug nintedanib was conducted in IPF and PPF, demonstrating its effectiveness in suppressing the decline in forced vital capacity (2, 3). The effect of nintedanib in slowing the progression of fibrosis, as observed in the INBUILD trial (4), was subsequently investigated and confirmed in numerous clinical studies involving patients in daily practice (5-14). However, most of these studies were conducted in patients with IPF (5-9), and only a few investigated the efficacy of nintedanib in patients with PPF (10, 12). Furthermore, these were based on the commonly used Gender-Age-Physiology (GAP) scoring system to classify the severity of ILD (5-10, 12).
To assess the severity of IPF, the GAP scoring system (15), an index designed to predict patient mortality, is often used. This system is based on respiratory function tests, which are effort-dependent, arterial blood gas tests, which are more invasive than standard venous blood sampling, and diffusion capacity tests, which require precision equipment to assess gas exchange capacity (15). It is estimated that in actual clinical practice, there are many patients for whom the GAP score system for ILD severity classification cannot be utilized due either to the patient’s physical condition, including respiratory status, or the lack of suitable equipment at the particular medical facility. The JRS has proposed a disease severity staging classification system for IPF (JRS staging), and this staging is now being used in clinical practice (16). While this system has been utilized in a study in patients with IPF (6), there has been limited evidence on its usefulness in PPF patients. This staging is a non-invasive evaluation, such as which includes measurement of arterial blood oxygen saturation, and can be used in patients and facilities where it may not be possible to perform the tests required for GAP scoring (6, 11, 16).
To our knowledge, there have been no detailed studies on the usefulness of nintedanib in patients who are excluded due to selection bias, including not only patients with IPF, but also patients with PPF. To clarify the usefulness of nintedanib in clinical practice, we collected information on patients with IPF and PPF and presented the results for patients who could be evaluated using the GAP score system (12). Among the patients collected at that time, there were many who could not be evaluated using the GAP score system due to patient factors or limitations of the medical facility, and these patients were excluded from the study. Among the excluded patients, 187 could have had their disease severity assessed using JRS staging. Therefore, we conducted a retrospective study to clarify the clinical utility of nintedanib in patients with ILD who were excluded due to selection bias involving invasive or specialized detailed examinations, i.e., in IPF and PPF patients commonly encountered in routine clinical practice.
Patients and Methods
Study population. All ILD patients treated with nintedanib at our nine medical institutions between August 2015 and December 2023 were identified from medical records. IPF was diagnosed according to the ATS/ERS/JRS/ALAT guidelines (1). Patients with PPF who met the criteria used in the INBUILD trial (4) were treated with nintedanib. A total of 445 patients with IPF and PPF met these criteria. Because the purpose of this study was to evaluate nintedanib treatment in patients whose disease severity was classified using noninvasive tests, patients with the following conditions were excluded: (i) patients who underwent pulmonary function and diffusion capacity tests before starting nintedanib and could be evaluated using the GAP score (n=235); and (ii) 23 patients for whom insufficient data set was available (Figure 1). The remaining 187 patients were included for analysis in this study.
Figure 1.
Study flow chart. IPF: Idiopathic pulmonary fibrosis; PPF: progressive pulmonary fibrosis.
ILD severity assessment. This study used JRS staging for IPF (16, 17). Staging was performed based on oxygen saturation of arterial blood measured by pulse oximeter (SpO2) in patients whose partial pressure of arterial oxygen (PaO2) was not measured by blood gas analysis. In brief, the severity of IPF and PPF has been classified into four stages: stage I (characterized by a resting PaO2 ≥ 80 Torr or SpO2 ≥ 90%); stage II (PaO2 70-79 Torr or SpO2 90-93%); stage III (PaO2 60-69 Torr or 90-93%); and stage IV (PaO2 < 60 Torr or SpO2 < 90%). If the resting PaO2 was grade I or II, and the minimum SpO2 during the 6-min walk test was less than 90%, the severity was classified as grade III. If the resting SpO2 was grade III, and the minimum SpO2 during the 6-min walk test was less than 90%, the severity was classified as grade IV (6, 16).
Nintedanib administration. Nintedanib was administered according to the recommended dosage and administration instructions. The duration of nintedanib administration was defined as the period from the start of administration to the final dose. Patients were classified into the following three groups based on nintedanib administration: (i) continuation group - patients who continued nintedanib administration throughout the study period without dose reduction or discontinuation; (ii) dose reduction group - patients whose nintedanib dose was reduced at least once during the initial administration or administration period, or who temporarily discontinued nintedanib; and (iii) discontinuation group - patients whose nintedanib administration was discontinued for any reason. Dose reduction and discontinuation of nintedanib were decided upon by the treating chest physician after consultation with the patient.
Acute exacerbations and evaluation of adverse drug reactions. The definition of acute exacerbation was based on the diagnostic criteria for acute exacerbation in IPF by Collard et al. (18). According to previous reports (19, 20), patients who survived for 90 days or more after the onset of an acute exacerbation were considered survivors. Adverse drug reactions were assessed according to the Common Terminology Criteria for Adverse Events version 6.0 (21), which is a method for evaluating adverse drug reactions to antitumor drugs. Adverse drug reactions requiring discontinuation of nintedanib were classified as grade 3.
Statistical analysis. The Mann-Whitney U test, Kruskal-Wallis test, and nonparametric tests were used to compare values. The chi-squared test was used to test for differences in proportions. Comparisons between groups were made using the chi-squared test and Mann-Whitney U test. Survival analysis was performed using the log-rank test and Cox’s proportional hazards model. A p-value of <0.05 was considered to indicate a significant difference.
Ethical Committee Approval. This retrospective study was approved by the ethics committees of Mito Medical Center, Tsukuba University Hospital, and Tsukuba University Hospital (approval number: NO 25-47), and by the participating medical institutions, and was conducted in accordance with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.
Results
Patient characteristics and nintedanib treatment outcomes. The average age at the start of nintedanib treatment for all 187 patients was 74 years (range=38-87 years), and 141 patients (75.4%) were male. During the 8-year study period, 96 patients (51.3%) discontinued nintedanib, with 68 (36.4%) of them discontinuing within one year of starting. During the 8-year study period, 35 patients (19.3%) experienced acute exacerbations. The median survival time from the start of nintedanib treatment was 43 months.
Comparison of patient characteristics by treatment group. Patients were divided into three groups based on their nintedanib administration status: continuation group (47 patients); dose reduction group (44 patients); and discontinuation group (96 patients). Table I shows the patient characteristics of these three groups. While there were tendencies for differences in ‘age’, ‘comorbidity with malignant tumors’, and ‘time from ILD diagnosis to initiation of nintedanib administration’; these differences were not statistically significant.
Table I. Patient characteristics of study population.
Values are number of patients, unless indicated otherwise. ILD: Interstitial lung disease; IPF: idiopathic pulmonary fibrosis; PPF: progressive pulmonary fibrosis; P: present; A: absent.
Nintedanib treatment, clinical course, and treatment results. Table II shows nintedanib treatment, clinical course, and treatment results. There was a significant difference in the duration of nintedanib administration among the three groups. There were also significant differences between the groups, with the continuation group having a significantly longer treatment period and the discontinuation group having a significantly shorter treatment period (continuation group vs. reduction group, p=0.03; continuation group vs. discontinuation group, p=0.01; reduction group vs. discontinuation group, p=0.01).
Table II. Nintedanib treatment, clinical course, and treatment results.
Values are number of patients, unless indicated otherwise. ILD: Interstitial lung disease; P: present; A: absent; AE: acute exacerbation.
Next, we analyzed the survival of the groups. There was a significant difference among the three groups in survival time from the start of nintedanib administration (p=0.01; Figure 2A). In comparisons between the groups, there was no significant difference between the continuation group and the reduction group (p=0.13), but significant differences were observed between the continuation group and the discontinuation group (p=0.01), and between the dose reduction group and the discontinuation group (p=0.01). The survival curves from ILD diagnosis are shown in Figure 2B. There was a significant difference in survival time among the three groups (p=0.01). Significant differences were observed between the groups in the following comparisons: between the continuation and reduction groups (p=0.03); between the continuation and discontinuation groups (p=0.01); and between the dose reduction and discontinuation groups (p=0.01).
Figure 2.
Survival from the start of nintedanib and from interstitial lung disease (ILD) diagnosis by patient group. (A) Survival curves from the start of nintedanib for the three groups. There is a significant difference in survival time among the three groups (p=0.01). While there is no significant difference between the continuation and reduction groups (p=0.13), significant differences are observed for all other comparisons (all p=0.01). (B) Survival curves from ILD diagnosis. There is a significant difference in survival time among the three groups (p=0.01). The survival time of the continuation group was significantly longer than that of the other two groups, while the survival time of the discontinuation group was significantly shorter than that of the other two groups (continuation group vs. reduction group, p=0.03; continuation group vs. discontinuation group, p=0.01; reduction group vs. discontinuation group, p=0.01). Survival curves were compared with log-rank test.
Significant differences were observed in the incidence of acute exacerbations among the three groups (p=0.01; Table II). In the comparison between the groups, while there was no significant difference between the reduction group and the discontinuation group (p=0.27), significant differences were observed between the continuation group and the reduction group (p=0.01), and between the continuation group and the discontinuation group (p=0.01).
The causes of death among the deceased patients were acute exacerbation, respiratory failure due to progression other than acute exacerbation, death from causes other than respiratory failure, and death from lung cancer. There was a significant difference in deaths from lung cancer among the three groups based on nintedanib administration status (Table II).
Adverse drug reactions and reasons for discontinuing nintedanib. Table III shows the adverse drug reactions among the three groups based on nintedanib administration. Diarrhea, liver dysfunction, and loss of appetite were the most frequent adverse drug reactions. The reasons for discontinuing nintedanib in the 96 patients were: worsening of the patient’s overall condition due to ILD, adverse drug reactions of nintedanib, patient’s request for discontinuation, and acute exacerbation (Table III).
Table III. The number of adverse drug reactions and reason for discontinuing nintedanib.
Poor prognostic factors. We investigated what factors were associated with “survival from ILD diagnosis” and “survival from nintedanib initiation.” In both analyses, not developing an acute exacerbation and nintedanib administration not being discontinued were identified as factors associated with longer survival (Table IV).
Table IV. Uni- and multivariate analysis of unfavorable factors in interstitial lung disease (ILD) patients.
HR: Hazard ratio; CI: confidence interval; BMI: body mass index; PPF: progressive pulmonary fibrosis.
Discussion
The distinguishing features of our study were that it included, not only patients with IPF, but also those with PD-ILD, and that by using JRS staging, we were able to evaluate the usefulness of nintedanib in a more general patient population that could not be assessed using GAP scores. Against this backdrop, the following findings were made: (i) This study suggests that continued administration of nintedanib might improve the outcomes for patients with IPF and PPF; (ii) The positive effects of nintedanib on reducing acute exacerbations of ILD, lung cancer development, and lung cancer-related deaths are worth investigating; (iii) As previously reported, gastrointestinal adverse reactions were frequent, highlighting the continued importance of developing effective measures to manage adverse drug reactions; and (iv) The impact of reducing the dosage of nintedanib on patient outcomes might also be a subject of future research.
In previously published studies evaluating the clinical usefulness of nintedanib, the surveys ranged in size from 97 to 430 patients, with most being in the 100-200 patient range (5-10). The median age of the patients was 71-74 years (5-10), and the proportion of men was 67%-87% (5-11). The age and sex of patients in the present study were similar to those in these previous studies. Most of the previous studies focused on verifying the usefulness of the treatment for patients with IPF (5-9). There have been only two reports on nintedanib treatment in both patients with IPF and patients with PPF; one by Andrisano et al. involving 97 patients (64 of whom had IPF) and another by Yazaki et al. involving 212 patients (165 of whom had IPF) (10, 12). However, both studies used GAP scores for evaluation (10, 12). Three studies have used JRS staging. These included a report by Iwasaki et al. on pirfenidone and nintedanib, a report by Sugino et al. focusing on JRS stage I patients, and a post-marketing surveillance study by Ogura et al. focusing only on JRS stage III/IV patients (6, 11, 13). However, these studies only included patients with IPF. Therefore, the present study is the first to evaluate patients with IPF and PPF using JRS staging.
Focusing on the discontinuation of nintedanib, previous studies have reported the discontinuation rate within one year of starting nintedanib to be 21.6%-51.0% (8, 10-12), and the discontinuation rate over the entire study period to be 28.3%-52.5% (5, 10, 14). The discontinuation rates of nintedanib in the present study fell within the range of these previous reports. Ogura et al. reported that ‘high severity’ was associated with early discontinuation in their post-marketing surveillance of nintedanib (11). Our study found that 68.3% of patients who discontinued nintedanib within one year of starting treatment had a JRS stage of III-IV, and 68.8% of all patients who discontinued treatment throughout the entire study period had a JRS stage of III-IV. Andrisano et al. reported that “discontinuation of nintedanib” and “stage III ILD (GAP score)” are poor prognostic factors for patients with ILD (10). It is very interesting that our study also found “discontinuation of nintedanib” to be a factor associated with poorer outcomes. Adverse drug reactions from nintedanib have been previously reported in 55.7%-83.6% of patients (5, 11), with diarrhea, nausea, and liver dysfunction being described as the most frequent reactions (5, 8). Previous studies show dose reduction of nintedanib has occurred in 28.3%-44.0% of patients (5, 10). Similar rates of adverse drug reactions and dose reduction of nintedanib were obtained in the present study.
The effect of nintedanib on the onset of acute exacerbations in ILDs is also noteworthy. Dobashi et al. reported that acute exacerbations occurred in 18.9% of patients in the moderate GAP score group, and 30.8% in the severe GAP score group (7). In a report by Iwasaki et al., 13.6% of patients experienced acute exacerbations during a 13-year observation period (13). The incidence of acute exacerbations might vary depending on patient characteristics and study period, making it difficult to generalize about high or low rates of acute exacerbation. The present study highlighted a high incidence of exacerbations in the nintedanib discontinuation group. While it is unclear whether nintedanib had efficacy in suppressing acute exacerbations, this was a noteworthy finding.
Limitations. Although it was a multicenter collaborative study, it was retrospective. The small study size and the appropriateness of the study and follow-up periods should also be mentioned as limitations. Specifically, the inclusion of patients with short durations of nintedanib administration and the lack of comparison with patients who did not receive nintedanib are limitations of this study. The lack of strict criteria for the indication, dose reduction, and discontinuation of nintedanib, and the use of the JRS staging classification (which has limited evidence for PPF) instead of GAP for severity assessment, are also limitations. Several studies (6-10, 12), including our own (12), have investigated the efficacy of nintedanib in patients with ILD who could be assessed using the GAP score. However, nintedanib might be sometimes administered to patients with ILD for whom such assessment could not be possible. Studies involving such patients could be prone to selection bias and methods lacking clarity and explicitness, potentially leading to studies with low scientific rigor. Therefore, we must take seriously the criticism that this study also had such limitations. Despite these limitations, we believe that we have conducted a meaningful study in patients with IPF and PPF, minimizing exclusion due to selection bias.
Conclusion
The results indicated that patients continuing nintedanib might receive positive effects on survival and the incidence of acute exacerbations. The results obtained in this study are considered worthy of further verification. As such, large-scale prospective studies in the future are desirable.
Conflicts of Interest
The Authors declare that they have no competing interests in relation to this study.
Authors’ Contributions
TK, MM, KM and HS designed the study. TK, KY MM, KM, TT, TN, SH, TI, YM, HS, and NK collected the data. MM, KM, TS and HS analyzed the data. KM and HS prepared the manuscript. HS and NH supervised this study. All Authors approved the final manuscript version for submission.
Acknowledgements
The Authors express their sincere gratitude to Shinichiro Okauchi, MD, PhD, for his outstanding statistical work.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
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