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• W2900867383 abstract "Idiopathic pulmonary fibrosis (IPF) is a severe chronic progressive lung disease that is becoming increasingly recognized, particularly in the elderly. IPF mortality remains high, with an unpredictable course of disease and specific treatments, that can, at best, halt but not cure the disease [1-4]. Pirfenidone and nintedanib are 2 antifibrotic agents that have revolutionized the approach to IPF over the last few years, with similar efficacy and safety profiles [1-3].Pirfenidone has been clinically investigated in IPF since almost 20 years. In 1999, an open-label, phase-II clinical trial demonstrated a stabilization of pulmonary function in 29 of 46 patients with IPF; including some with very severe disease [5]. Most of the patients were treated with prednisone, cyclophosphamide, or azathioprine at study entry; in hindsight, the stabilization with pirfenidone treatment was at least partially due to the discontinuation of these immunosuppressive drugs during the study. Thirteen years later, the PANTHER trial clearly demonstrated an increased risk of mortality in IPF patients treated with the immunosuppressive regimen [6]. In 2011 and 2014, pirfenidone was officially approved for the treatment of IPF in Europe and the USA, by then, the drug had demonstrated clinical efficacy in several phase-III clinical trials, with a stabilization of the decline of lung function in treated patients and evidence of a reduction in mortality risk in the post hoc analyses [1, 2, 7].Patients with severely impaired pulmonary function (forced vital capacity [FVC] < 50%-predicted and/or diffusing capacity of the lung for carbon monoxide [DLCO] < 30%-predicted) have been excluded from phase-III pharmacological trials. Unfortunately, there is no standardized definition of advanced or severe IPF, but in real-life cohorts > 20% of patients are stratified as GAP (Gender, Age, and Physiology) index stage III, and the body of evidence on benefit and harm of antifibrotic therapy in this important minority is weak [8-10].In this issue of Respiration, Yoon et al. [11] report their observations on the safety and effectiveness of treatment with pirfenidone in patients with severely impaired pulmonary function. They compared the frequency of adverse events in 37 patients with advanced IPF and 101 patients with nonadvanced IPF. Reassuringly, the authors reported no new adverse effects. Serious adverse events including death were more frequently observed in patients with advanced disease, with disease stage and not antifibrotic treatment being the likely reason for this difference in outcome. Equally important, in the subgroup of patients with advanced IPF the potential for lower medication tolerability was demonstrated, including an increased treatment duration adjusted odds for minor adverse events such as anorexia and constipation, a shorter time to the development of these events, and more frequent dose reduction, treatment interruption, or pirfenidone discontinuation. Furthermore, the comparable effectiveness of pirfenidone in both IPF severity groups suggests a similar benefit from treatment in advanced and mild-to-moderate IPF, with the assumption that slowing down FVC decline translates to fewer symptoms, a better quality of life, and/or a reduction in mortality in advanced IPF patients. Lastly, the study gives us an insight into how advanced IPF patients differ from those with mild-to-moderate IPF. The more frequent treatment with corticosteroids for example, might reflect a higher risk for polypharmacy, potentially reducing the overall tolerability of and adherence to antifibrotic treatment. The more frequent smoking, lower body mass index, poorer physical performance, and more frequent pulmonary hypertension point towards a higher burden of comorbidity and frailty, potentially increasing patients’ susceptibility to clinically significant adverse reactions to medication. Unlike in randomized controlled trials (RCTs), these individual patient factors cannot be controlled for in observational studies, such as this one [11].RCTs are the backbone of evidence-based medicine and are known for their excellent internal validity which is essential to determine treatment efficacy. Strict inclusion and exclusion criteria aim to select patients with a typical clinical presentation who are only minimally impacted by comorbid diseases. Typically, RCTs include patients likely to experience disease progression without effective treatment, which limits costs and shortens trial duration, but also limits the generalizability of the results. This leaves us with a black box of uncertainty on how to approach patients with characteristics different from those included in RCTs. Notably, the RCTs that led to the approval of pirfenidone had high screening failure rates (44/39% in CAPACITY I/II [2] and 64% in ASCEND [1], with 13 and 11% of the screened IPF patients not meeting the FVC and DLCO criteria, respectively); this gives us an estimate of how many patients in clinical practice would be excluded from these trials.Open-label extension studies help to narrow the gap between efficacy and effectiveness; the RECAP study, for instance, provided essential safety information on long-term pirfenidone treatment [12]. However, phase-IV patient populations still do not reflect real-world IPF populations, with exclusion of patients with severe comorbidities at enrolment in phase III, close follow-up during phase III, and treatment-naivety in only half of the study cohort, potentially introducing a selection bias towards the patients who tolerate pirfenidone well. Real-world observational studies, on the other hand, also have major limitations and a multitude of biases that potentially skew conclusions, particularly if results are considered in isolation from RCTs. However, they do provide valuable evidence on how antifibrotics work in clinical practice, and which factors need to be included in clinical decision-making when faced with the uncertainty of an individual patient who does not fulfil the RCT inclusion criteria [11, 13-15].In 1927, Heisenberg [16] described the uncertainty principle in quantum mechanics, stating that a particle’s position and momentum cannot be determined simultaneously. If trapped in a box, the uncertainty in the position of the particle is proportional to the width of the uncertainty box. Translated to the physical human world and specifically the difficulties we face in our efforts to change the course of disease in an IPF patient, we know that it is very challenging to pinpoint the position of an IPF patient on their disease and FVC trajectory and that the momentum (FVC decline) cannot be predicted from the past trajectory [4]. Diagnostic and therapeutic uncertainty are omnipresent in interstitial lung disease, but the growing body of evidence from RCTs, observational cohorts, and registry studies contributes to the shrinkage of the black box of uncertainty surrounding the potential benefits and harms of antifibrotic treatments.With more evidence on patient-specific factors available, physicians can more carefully balance different factors to confidently face clinical decisions and discussions on potential therapeutic options with the patient (Fig. 1). Besides pharmacological treatment, we should not neglect nonpharmacological management strategies, such as long-term oxygen therapy, adequate management of comorbidities, and pulmonary rehabilitation including education and psychological support of patients and caregivers as well as palliative care [17]." @default.
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• W2900867383 date "2018-11-19" @default.
• W2900867383 modified "2023-09-25" @default.
• W2900867383 title "Antifibrotics: Shrinking the Box of Therapeutic Uncertainty" @default.
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