|Year : 2023 | Volume
| Issue : 1 | Page : 45-51
|Nintedanib and pirfenidone for idiopathic pulmonary fibrosis in King Abdulaziz Medical City, Riyadh: Real-life data
Mohammed Ayaz Khan1, Nahed Sherbini2, Sami Alyami1, Abdullah Al-Harbi1, Majed Al-Ghamdi1, Suliman Alrajhi3, Rajkumar Rajendram4, Hamdan Al-Jahdali1
1 Department of Medicine, College of Medicine, King Saud University for Health Sciences; King Abdullah International Medical Research Centre; Department of Medicine, Division of Pulmonary, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
2 Department of Medicine, College of Medicine, King Saud University for Health Sciences; King Abdullah International Medical Research Centre; Division of Pulmonology, Prince Mohammed bin Abdulaziz Hospital, National Guard Health Affairs, Madina, Saudi Arabia
3 Department of Medicine, College of Medicine, King Saud University for Health Sciences; King Abdullah International Medical Research Centre; Department of Radiology, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
4 Department of Medicine, College of Medicine, King Saud University for Health Sciences; King Abdullah International Medical Research Centre; Department of Medicine, Division of Internal Medicine, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
|Date of Submission||30-May-2022|
|Date of Decision||31-Jul-2022|
|Date of Acceptance||04-Aug-2022|
|Date of Web Publication||25-Jan-2023|
Dr. Hamdan Al-Jahdali
McGill University, Montreal, Canada, Division of Pulmonary, King Saud University for Health Sciences, Riyadh; Sleep Disorders Center, King Abdulaziz Medical City, Riyadh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive age-related lung disease causing relentless fibrosis of the lung parenchyma. Currently, pirfenidone and nintedanib are the two antifibrotic drugs, approved for the treatment of IPF. Both are shown to slow progression by preserving lung functions from rapid decline compared to a placebo. We are reporting a real-life patient experience using these two antifibrotic medications (AFMs) in our tertiary care hospital.
METHODS: A retrospective cohort study was conducted for all IPF cases diagnosed in multidisciplinary meetings between 2015 and 2020 at KAMC, Riyadh (Saudi Arabia). We are reporting patients' demographics, lung function, survival, tolerance, side effects, or death in patients taking AFMs.
RESULTS: A total of 81 cases were identified. The majority of patients aged 67 years (68%) were men with a median age of 68 years. Late presentation, severe disease, and definite usual interstitial pneumonia patterns were reported in 60% of our patients. The average number of hospital admissions before starting treatment was 1 (range: 0–3) in the nintedanib group and 1.4 (range: 1.2–5) in the pirfenidone group. There was an increase in the number of hospital admissions in the group started on pirfenidone 1.7 (range: 1.9–8) compared to nintedanib 0.5 (range: 0–3), P = 0.001. The observed mortality outcome in this cohort was 4 (11%) and 12 (27%) for nintedanib and pirfenidone, respectively. The predominant side effects were gastrointestinal symptoms for both the groups 18 (22%).
CONCLUSIONS: Pirfenidone and nintedanib are the available approved antifibrotic agents used for many years to treat IPF patients. Real-life data showed better tolerability than reported in the West, good compliance, and a manageable side effect profile in this group of elderly and severe IPF patients.
Keywords: Drug side effects, idiopathic pulmonary fibrosis, mortality, nintedanib, pirfenidone, safety, tolerability
|How to cite this article:|
Khan MA, Sherbini N, Alyami S, Al-Harbi A, Al-Ghamdi M, Alrajhi S, Rajendram R, Al-Jahdali H. Nintedanib and pirfenidone for idiopathic pulmonary fibrosis in King Abdulaziz Medical City, Riyadh: Real-life data. Ann Thorac Med 2023;18:45-51
|How to cite this URL:|
Khan MA, Sherbini N, Alyami S, Al-Harbi A, Al-Ghamdi M, Alrajhi S, Rajendram R, Al-Jahdali H. Nintedanib and pirfenidone for idiopathic pulmonary fibrosis in King Abdulaziz Medical City, Riyadh: Real-life data. Ann Thorac Med [serial online] 2023 [cited 2023 Mar 20];18:45-51. Available from: https://www.thoracicmedicine.org/text.asp?2023/18/1/45/368496
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia that causes fibrosis with scarring of the lungs from an unknown cause, though the exact mechanisms of damage in IPF remain poorly understood. It is usually a progressive disease with a poor prognosis (median survival of 3–5 years after diagnosis if untreated), and the 5-year survival is 20%–40%.,, Chest computed tomography scan is a hallmark for diagnosis with a classical peripheral basal distribution of bilateral interstitial reticulation and fibrosis with usual interstitial pneumonia (UIP) and correlates well with histopathological UIP pattern. Alhamad et al. reported independent association between advanced age, IPF diagnosis, reduced forced vital capacity (FVC), and low cardiac index in cohort of interstitial lung disease (ILD) Saudi patients. Furthermore, acute exacerbation was one of many independent risk factors associated with worsened outcomes regardless of the underlying ILD type. Unfortunately, there is a significant delay between the onset of symptoms and diagnosis ranging from 1 to 48 months.
The aim of IPF management is mainly, early diagnosis of ILD, to improve the respiratory functional capacity of patients and to stabilize or reduce the rate of disease progression.,
Pirfenidone and nintedanib are the only disease-modifying treatments available for IPF as internationally recommended. A number of landmark studies were done to investigate the efficacy of these antifibrotic medications (AFMs). Phase III clinical trials ASCEND, CAPACITY, and TOMORROW followed by INPULSIS trials.,,, The ASCEND trial of pirfenidone in patients with IPF and mild or moderate impairment in lung function at baseline showed that it reduced the rate of decline in FVC over 1 year by approximately 50%. The TOMORROW trial revealed that nintedanib slowed the progression of the disease, and a 68% reduction in the annual FVC decline rate for nintedanib-treated patients compared to a placebo group and a reduction in the number of acute exacerbations in treated compared to untreated patients. The INPULSIS studies consistently demonstrated the efficacy of nintedanib in reducing disease progression with a significant reduction in the annual decline in FVC by about 50%. More interestingly, a meta-analysis of the phase 3 ASCEND and CAPACITY trials and 2 Japanese trials (Shionogi) of pirfenidone vs. placebo showed that pirfenidone reduced the risk of all-cause mortality (hazard ratio [HR], 0.52; P = 0.01) and IPF-related mortality (HR, 0.35; P = 0.003). These trials provided important information regarding the efficacy and safety of antifibrotics in patients with IPF. However, the nature of clinical trials with strict inclusion and exclusion criteria, particularly excluding severe IPF cases and cases with comorbidities, may limit the generalization of the results to real-world populations of patients with IPF. Different real-world IPF studies have reported different results. For example, real-world PROOF registry enrolled a total of 277 patients. Mortality was 23.1% and 5.4% of the patients experienced an acute exacerbation. A temporary dose discontinuation reported in 12.9%, temporary dose reduction reported in 31.8% and 4.3% of patients had permanently discontinued pirfenidone due to an adverse drug reaction. Another real-life study by Noor et al. revealed that pirfenidone and nintedanib were associated with a higher median survival post diagnosis compared to the untreated cohort of 3.5, 3, 3.75, and 2.5 years, respectively, while a real-life study by Wright et al. revealed that there was no significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (P = 0.132) after 12 months of antifibrotic use.
Both antifibrotic pirfenidone and nintedanib were approved in Saudi Arabia by Saudi Food and Drug Administration for treatment of IPF. Pirfenidone has been prescribed by the KAMC since March 2014 and nintedanib since December 2015.
The purpose of our current study was to evaluate the basic characteristics of nontrial, "real-life" patients on either antifibrotic treatment. The clinical and functional characteristics of IPF patients treated with pirfenidone or nintedanib were recorded to define the effectiveness of antifibrotic therapy and then compared with data in the literature. We aimed to test their efficacy, tolerability, and safety during our routine clinical practice.
| Methods|| |
A single-center retrospective cohort study included all Saudi IPF patients on pirfenidone or nintedanib since March 2014 until the end of 2020. All cases were diagnosed with IPF according to ATS/ERS/JRS/ALAT 2011 guidelines after discussion in ILD multidisciplinary team (MDT) meetings among pulmonologists, dedicated thoracic radiologists, and pathologists.
The decision regarding the suitability of AFM was discussed with patients and their families and treatment began after their consent. Both pirfenidone and nintedanib were prescribed as per the manufacturer's recommendations. Pirfenidone was titrated to a dose of 801 mg three times a day (2403 mg total/day) as tolerated and nintedanib was prescribed at 150 mg twice a day. Pulmonary function tests (PFTs), full blood count, urea and electrolyte, and liver function tests were done in all patients prior to commencing therapy and then again periodically during clinic visits. The clinic review would assess patient compliance, dose confirmation or adjustment, side effect profile, any intervening infections, and hospital admissions for all episodes.
Institutional Review Board approval from King Abdullah international medical research center (KAIMRC) was obtained. Variables were collected from the electronic patient records included demographics, drug tolerability outcomes including discontinuation of the treatments, adverse effects (AEs), type and severity of AEs, PFTs, survival, and progression defined as a 10% reduction in FVC. Other parameters collected were clinic visits, hospital admissions, emergency room visits, and deaths while on AFM.
- Inclusion: Adult patients (aged >18 years) diagnosed as IPF, based on MDT meetings consensuses
- Exclusion: All other ILDs as decided by ILD MDT to be inconsistent with IPF.
Data were analyzed using IBM SPSS for Windows, version 18.0 (Armonk, NY-USA: IBM Corp). The frequency of IPF cases of those who either received pirfenidone or nintedanib and the percentage of resulting deaths were also calculated.
Statistical analyses of demographic, clinical, physiological, and laboratory descriptive data are tabulated. Descriptive statistics such as means and standard deviation mean (±SD) were used to describe the age of the patients, laboratory test results, and duration of illness and treatment. Frequencies and percentages n (%) were used to describe demographics and outcomes. We also did a correlation with the outcome using the t-test and Fisher's exact test as appropriate with a significant value at P ≤ 0.05.
| Results|| |
The total number of cases with confirmed IPF as reported from March 2014 for starting antifibrotics medications (AFMs) in KAMC was 81. Pirfenidone was used in our institution before nintedanib was approved which is the reason for a slightly higher number of cases on former's treatment. There was no statistical difference between the groups on AFM with regard to age, gender, smoking status, or pattern of definite, or probable UIP on the CT scan, as shown in [Table 1]. The majority of patients aged 67 years (68%) were men with a median age of 68 years. Current smokers were only 6% of the group while patients who had never smoked consisted of more than 60%. Radiological CT findings of UIP were reported as definite or probable in 30 (83%) patients in the nintedanib group and 42 (93%) patients in the pirfenidone group. There was a significant difference in those who underwent surgical lung biopsy to confirm the diagnosis in the group taking nintedanib compared to pirfenidone (14 [39%] vs. 7 [16%], P = 0.02). The average time from referral to completing the diagnostic work and start of AFM was an average of 4 months (mean ± SD).
PFT done in 55 patients (69%), 26 patients (32%) either were not able to perform PFT or excluded due to poor quality. The two treatment groups were comparable with no significant difference in baseline FVC, diffusion capacity for carbon monoxide transfer factor (DLCO), 6-min walking test (6MWT), and arterial blood gas (ABGs) before starting the treatment, as shown in [Table 2]. Both the groups demonstrated a mean FVC of 60% predicted (range: 32%–82%) and a DLCO of 52% predicted. Where ABG data were available, 40% in the nintedanib group and 58% in the pirfenidone group showed respiratory failure with hypoxia. This signifies moderate-to-severe functional impairments and a more severe disease presentation in this cohort. The 6MWT recorded an average of a 275-m walking distance with more desaturations observed in the nintedanib group compared to the pirfenidone group (30 [83%] vs. 20 [44%], P < 0.001). These physiological severities are reflected in that the majority of patients in the nintedanib and pirfenidone groups were on home supplement oxygen therapy, 31 (86%) and 40 (89%), respectively. Pulmonary rehabilitation (PR) is a unique program in KAMC and is offered to the majority of patients with ILDs in general and IPF in particular. The current cohort completed PR for 47% in the nintedanib group and 44% in the pirfenidone group, as shown in [Table 2].
Clinical outcome measures and mortality
Our cohort included mostly severe IPF patients with impaired physiology with most of the study population on home supplement oxygen. Most of our patients were elderly and presented with severe diseases and thus some of the PFTs were difficult to obtain in this real-life cohort. The baseline and some serial recordings of physiological data were available, but we could not record all the follow-up data. Patients were either unable to perform the PFTs or attempts were not adequate to include them in the record due to frailty. We looked at other clinical parameters such as the number of hospital admissions before and after the diagnosis of IPF for any cause, the number of clinical visits, and the duration of treatment and mortality in this cohort data shown in [Table 3]. The average number of hospital admissions before starting treatment was 1 (range: 0–3) in the nintedanib group and 1.4 (range: 1.2–5) in the pirfenidone group. There was an increase in the number of hospital admissions in the group started on pirfenidone 1.7 (range: 1.9–8) compared to nintedanib 0.5 (range: 0–3), P = 0.001. The average number of clinic visits remained was the same in both the nintedanib and pirfenidone groups after the start of respective therapies (mean: 4.1) visits. The duration of AFM observed after the start was an average of 22 months for nintedanib and 37 months for pirfenidone. The majority of patients in both nintedanib 34 (94%) and pirfenidone 36 (80%) were on proton-pump inhibitors (PPIs). The observed mortality outcome in this cohort was 4 (11%) and 12 (27%) for nintedanib and pirfenidone, respectively. We found that advanced age, an increasing number of hospital admissions, and oxygen desaturation on 6MWT are a predictor of mortality with a significant P value, as shown in [Table 4].
The majority of the cohort tolerated AFM-nintedanib and pirfenidone, well with no significant side effects. Adverse events reported were predominantly gastrointestinal (GI) symptoms, mainly nausea and vomiting in both the groups with nintedanib presenting predominantly lower GI and pirfenidone presenting upper GI. The major side effect reported for nintedanib was diarrhea in five patients (14%) followed by combined diarrhea and nausea in 4 (11%). Pirfenidone therapy was associated with AEs of nausea in 5 cases (11%) and vomiting in 4 cases (9%) while weight loss, dyspepsia, and photosensitive rash were also observed in a few cases, as shown in [Table 5]. Overall, only two patients were switched from nintedanib to pirfenidone due to troublesome diarrhea. Overall, the cohort tolerated both AFMs well with a manageable AE profile.
Our cohort showed that more than 65 (65%) of these real-life patients had 2 or more comorbidities. Most of these were cardiorespiratory in nature. This is much higher than reported by Cerri et al. where the comorbidities recorded were 48%.
| Discussion|| |
We demonstrated a real-life experience with the use of nintedanib and pirfenidone in this study. Similar to a previous study by Alhamad et al., our patient population presented with more advanced disease, the majority of which were nonsmokers and had significant comorbidities (65% two or more comorbid conditions). Raghu et al. reported a wide range of nonrespiratory comorbidities in their systemic review 68%. They also reported, in the same study, the prevalence of Gastroesophageal reflux disease (GERD) 0%–94% that is again a wide range. Our real-life patients were on PPIs in 87% of the cases which is in line with the upper range as reported by Raghu et al. This was a well-worked up cohort with all patients being discussed and a combined decision being taken in ILD MDT with dedicated team members. The patient characteristics and comorbidities are similar to another published larger population reported by Essam Alhamad in a recent paper. Our cohort was physiologically more impaired and advanced with 87.6% of patients in both the groups taking supplemental oxygen therapy. This is significantly higher compared to other larger studies. Dempsey et al. reported 58% of their large cohort on supplement oxygen, while the ASCEND trial reported that 28% of their patients needed home oxygen. Surgical lung biopsy was performed on about a quarter (27%) of the overall group with more so in the nintedanib group. This might reflect those patients where clinical features or CT appearance are not typical of IPF (CT presents more of a probable or inconsistent picture) and where a biopsy was recommended for a diagnosis as per guidelines. We have limited information on serial progress on PFTs due to this cohort's advanced nature of the disease resulting in an inability or unwillingness to perform PFTs. We also used other parameters such as hospital admissions or ER visits, outpatient clinic visits, survival, and mortality data in this cohort. There was a trend toward an increasing number of hospital admissions in the pirfenidone group. This is probably due to the progression of IPF and other comorbidities.
The data mentioned above by Dempsey et al. observed that the efficacy of pirfenidone declined over time and we wonder if this could be true of our cohort with progression and further hospital admissions. The reason for this observation is not very clear. Our real-life cohort represents an elderly and severe group of IPF that is different from the trial population of pirfenidone and nintedanib where the participants were included with mild-to-moderate IPF. Our cohort seems to have benefited from both AFMs in terms of survival as reported in other large studies. Lancaster et al. performed pool analyses of six studies with regard to nintedanib safety and survival where survival benefit was reported in patients taking AFMs. The median survival was estimated as 8.5 years in the nintedanib group and 3.3 years in the placebo group. Kolb et al. reported in their study that the addition of sildenafil to nintedanib did not improve the quality of life measuring St. George's respiratory questionnaire (SGRQ), but other secondary endpoints of survival and less number of acute exacerbations were observed. Holtze et al. reported in a large US registry reported that the use of AFM in the elderly seems to have been associated with negative outcomes in quality of life and survival. On the other hand, a large German study reported by Leuschner et al. did not find any significant difference in benefits based on the age of the patient with IPF. Our cohort of IPF tolerated AFM well with a mean duration of 2 years and 4 months for both the groups. This reflects that benefit was present in this group of patients irrespective of their age and severity of their disease. The majority of our patients were on PPI therapy which is common in IPF patients. Our data showed good tolerability and safety of both AFMs – nintedanib and pirfenidone.
Men were more commonly affected as noticed previously as well as in our findings, and the nature of the diseases varies between the patients.
The majority of the side effects were GI in nature with pirfenidone therapy associated with upper GI symptoms such as nausea, loss of appetite, and vomiting. Nintedanib use was associated with lower GI side effects such as diarrhea, abdominal pain, and nausea. The types of AEs were similar to the reports from other clinical trials of pirfenidone CAPACITY, ASCEND, and nintedanib-INPULSIS.
The frequency in our real-life patients is not that much higher than reported in the aforementioned trials perhaps due to not looking for AEs in real-life patients when compared to trial populations where AEs are recorded more stringently. We were reassured that the use of nintedanib was not associated with a higher frequency of diarrhea that needed discontinuation of treatment except in two patients. This perhaps may also be due to dietary factors in Saudi Arabia varying from other parts of the world. Our cohort has good compliance with both treatment regimens and contrary to some other studies that reported discontinuation of AFM in elderly and severe cases., We did not note this observation in our population. We demonstrated in our study population that advanced age, number of hospital admissions, and 6MWT desaturations are risk factors for mortality in line with other published data. The major limitations of our study were single-center experiences and the lack of a complete record for FVC and DLCO, due to the retrospective nature of the study.
| Conclusions|| |
IPF is chronic progressive fibrosing ILD of unknown etiology. The currently recommended treatments; pirfenidone and nintedanib were well tolerated in our cohort of real-life patients. This retrospective data over an average of 2.4 years for AFM demonstrate good patient compliance, safety profile, and low discontinuation rates in line with published data. This is even more important considering our study population was severe and elderly with significant comorbidities and physiological limitations. Advanced age, number of hospital admissions, and significant oxygen desaturations were associated with mortality in our cohort.
All authors wrote the manuscript. All authors read and approved the final manuscripts.
Authors' contributions: HJ, MAK, NS, and SA participated in the study concepts, design of the study, and development of the questionnaire. A data acquisition and entry. AH, HJ, MG, and SA contributed in data analysis and statistical analysis of the data, participated in the intellectual content, and reviewed and summarized the published literature and clinical studies. MAK and RR participated in outlining the result themes and manuscript preparation, editing, and review. Corresponding author HJ takes responsibility for the integrity of the work as a whole. All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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