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      Nintedanib and Sildenafil in Patients with Idiopathic Pulmonary Fibrosis. Echoes of the Past, Lessons for the Future

      editorial
      , M.D. 1
      American Journal of Respiratory and Critical Care Medicine
      American Thoracic Society

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          Abstract

          Pulmonary hypertension (PH) commonly complicates the course of patients with idiopathic pulmonary fibrosis (IPF). It is associated with impaired functional ability and worse survival (1). The prevalence of PH has a variably reported range between 15% in those with mild to moderate restriction and 84% in those with more advanced disease (2, 3). The high end of this range underscores that most patients are likely to develop PH as their disease progresses. The increasing armamentarium of drugs to treat pulmonary arterial hypertension has raised the notion of therapy for PH complicating IPF. It remains uncertain whether the presence of PH is the driver of worse outcomes or whether it is a surrogate for disease severity. If it is indeed an adaptive phenomenon, then ameliorating this may not result in benefit and, worse yet, might result in harm. In contrast, if PH in this setting is a maladaptive response, then targeting it may result in beneficial outcomes. The INSTAGE (Efficacy and Safety of Nintedanib Co-administered with Sildenafil in Idiopathic Pulmonary Fibrosis Patients with Advanced Lung Function Impairment) study was a prospective, double-blind, randomized clinical trial comparing the benefits of nintedanib with those of nintedanib plus add-on sildenafil in patients with IPF with single-breath Dl CO <35% predicted (4). This major inclusionary criterion replicated that of the STEP-IPF (Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis) study, which examined the effects of sildenafil versus placebo in patients with IPF (5). Among patients with IPF with Dl CO <35%, the prevalence of PH is about 50%, and in this regard, this cutpoint represents an enrichment strategy for underlying resting PH (6). The INSTAGE study failed to meet its primary endpoint of a change in the St. George’s Respiratory Questionnaire at 12 weeks, but there was a favorable trend in a number of secondary endpoints, including the University of California, San Diego, Shortness of Breath questionnaire, as well as a salutary effect on FVC change. Therefore, although it was a negative study based on the chosen primary endpoint, the INSTAGE study was suggestive of a possible benefit, perhaps best demonstrated in a further enriched population. In this issue of the Journal, Behr and colleagues (pp. 1505–1512) present a post hoc analysis of the INSTAGE cohort, categorized by the presence or absence of echocardiographic evidence of right heart dysfunction (RHD) (7). This parallels a subgroup analysis of the STEP-IPF study, which demonstrated a significant improvement in 6-minute-walk distance of 99 m in the sildenafil patients who had evidence of RHD on echocardiography (8). Thus, the current subgroup analysis was eagerly anticipated, with the hope that this too might demonstrate a similar difference. Moreover, a positive result would have further established echocardiography as a complimentary enrichment strategy that, coupled with the Dl CO, could identify patients with IPF who were likely to benefit from sildenafil. Unfortunately, however, the presence of RHD did not appear to predict benefit from nintedanib plus sildenafil over nintedanib alone. Notably, there was no difference in the effects of combined therapy in those with RHD with regard to the primary endpoint (St. George’s Respiratory Questionnaire score), or secondary endpoints including the University of California, San Diego, Shortness of Breath questionnaire or change in FVC. Indeed, the only difference between the two groups was a change in the B-type natriuretic peptide, with greater stabilization of this biomarker noted in the RHD group receiving combined therapy. The disappointing message from this subgroup analysis is that those with RHD did not have a magnified response when treated with sildenafil. Why did evidence of RHD on echocardiography not discern an enriched target group for sildenafil therapy? One possible explanation could be insufficient standardization or reader variability between participating centers, as there were no central reads of the echocardiograms. We have certainly learned the value of central adjudication of high-resolution computed tomography scans for inclusion in IPF studies (9). If RHD is to be the target of a subgroup analysis in future clinical trials, then perhaps the same due diligence for echocardiography studies should be applied. This may be especially important in patients with IPF and other forms of advanced lung disease, given the disappointing performance characteristics of echocardiography in determining PH in these patients (10, 11). On the flip side of this negative subgroup analysis, a potentially heartening message is that if sildenafil does indeed benefit patients with Dl CO <35%, then everyone may be a candidate, not just those with RHD. Indeed, although there may not be evidence of PH at rest, many of these patients with Dl CO <35% likely do have exercise-induced PH (12). Another possible reason for the failure of echocardiography to discern a target group is that perhaps the quality-of-life benefit suggested by the INSTAGE study was not a result of the vasodilatory properties of sildenafil but, rather, the synergistic antifibrotic properties of sildenafil coupled with nintedanib, suggested by the lack of deterioration in the FVC in the dual-therapy group (4). Whether the suggested benefits of sildenafil together with nintedanib will be seen in a broader population of patients with IPF (e.g., Dl CO >35%) remains uncertain. Similarly, whether similar or more robust results will be seen with the combination of pirfenidone and sildenafil remains unknown but is eagerly anticipated (13). The encouraging news from the INSTAGE study, reinforced by this current subgroup analysis, is that patients with IPF with severe disease are a worthy study population. These patients have typically been excluded from prior pharmaceutical clinical trials and have limited options. They are therefore readily available, recruitable, and retainable with a clinical course that is inevitable. In addition, patients with more severe disease do not appear to be at unduly heightened risk for treatment-related adverse events. The inclusion of patients with more severe disease may be a valuable enrichment strategy when evaluating future pharmacologic therapies for IPF. This is especially important in the current era, in which antifibrotic therapy is the established standard of care resulting in a more attenuated disease trajectory. In the phase 3 INPULSIS studies, 30% of patients with mild to moderate disease when receiving nintedanib had a 10% FVC decline at 52 weeks, whereas in the INSTAGE study of patients with more advanced IPF, 36.8% of patients receiving nintedanib met the endpoint of a 10% relative FVC decline or death at 24 weeks (7, 9). Patients with IPF with more advanced disease therefore have a higher event rate, which may enable shorter studies with fewer patients required to power a difference (14). There is often a silver lining and much to be gained from negative studies; in this regard, it is hoped that the INSTAGE study and the current subgroup analysis will help set the stage for future studies focusing on the later part of the IPF journey.

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          Most cited references12

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          A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis.

          Sildenafil, a phosphodiesterase-5 inhibitor, may preferentially improve blood flow to well-ventilated regions of the lung in patients with advanced idiopathic pulmonary fibrosis, which could result in improvements in gas exchange. We tested the hypothesis that treatment with sildenafil would improve walk distance, dyspnea, and quality of life in patients with advanced idiopathic pulmonary fibrosis, defined as a carbon monoxide diffusion capacity of less than 35% of the predicted value. We conducted a double-blind, randomized, placebo-controlled trial of sildenafil in two periods. The first period consisted of 12 weeks of a double-blind comparison between sildenafil and a placebo control. The primary outcome was the proportion of patients with an increase in the 6-minute walk distance of 20% or more. Key secondary outcomes included changes in oxygenation, degree of dyspnea, and quality of life. The second period was a 12-week open-label evaluation involving all patients receiving sildenafil. A total of 180 patients were enrolled in the study. The difference in the primary outcome was not significant, with 9 of 89 patients (10%) in the sildenafil group and 6 of 91 (7%) in the placebo group having an improvement of 20% or more in the 6-minute walk distance (P=0.39). There were small but significant differences in arterial oxygenation, carbon monoxide diffusion capacity, degree of dyspnea, and quality of life favoring the sildenafil group. Serious adverse events were similar in the two study groups. This study did not show a benefit for sildenafil for the primary outcome. The presence of some positive secondary outcomes creates clinical equipoise for further research. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00517933.)
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            Echocardiographic assessment of pulmonary hypertension in patients with advanced lung disease.

            Doppler echocardiography is commonly used to estimate systolic pulmonary artery pressure and to diagnose pulmonary hypertension, but data relating to its utility in patients with advanced lung disease are limited. In a cohort study of 374 lung transplant candidates, the performance characteristics of echocardiography compared with right heart catheterization in the determination of systolic pulmonary artery pressure and diagnosis of pulmonary hypertension were investigated. The prevalence of pulmonary hypertension was 25% in the study population. Estimation of systolic pulmonary artery pressure by echocardiography was possible in 166 patients (44%). The correlation between systolic pulmonary artery pressure estimated by echocardiography and measured by cardiac catheterization was good (r = 0.69, p < 0.0001). However, 52% of pressure estimations were found to be inaccurate (more than 10 mm Hg difference compared with measured pressure), and 48% of patients were misclassified as having pulmonary hypertension by echocardiography. Sensitivity, specificity, and positive and negative predictive values of systolic pulmonary artery pressure estimation for diagnosis of pulmonary hypertension were 85%, 55%, 52%, and 87%, respectively. In conclusion, despite a statistically significant correlation with directly measured values, estimation of systolic pulmonary artery pressure by echocardiography is frequently inaccurate in patients with advanced lung disease and leads to considerable overdiagnosis of pulmonary hypertension.
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              Nintedanib plus Sildenafil in Patients with Idiopathic Pulmonary Fibrosis

              Nintedanib is an approved treatment for idiopathic pulmonary fibrosis (IPF). A subgroup analysis of a previously published trial suggested that sildenafil may provide benefits regarding oxygenation, gas exchange as measured by the diffusion capacity of the lungs for carbon monoxide (DlCO), symptoms, and quality of life in patients with IPF and severely decreased DlCO. That idea was tested in this trial.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                15 December 2019
                15 December 2019
                15 December 2019
                15 December 2019
                : 200
                : 12
                : 1459-1461
                Affiliations
                [ 1 ]Advanced Lung Disease and Lung Transplant Program

                Inova Fairfax Hospital

                Falls Church, Virginia
                Article
                201908-1510ED
                10.1164/rccm.201908-1510ED
                6909842
                31425662
                3fa84a1f-c15a-4335-a73d-89bc66d5e973
                Copyright © 2019 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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