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Tamera J Corte - One of the best experts on this subject based on the ideXlab platform.
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impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and Idiopathic Interstitial Pneumonia a post hoc subgroup analysis of the rise iip study
Journal of Heart and Lung Transplantation, 2021Co-Authors: Steven D Nathan, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, H Leuchte, Anne M Keogh, Nesrin Mogulkoc, Silvia UlrichAbstract:BACKGROUND RISE-IIP, a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP), was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography (HRCT), and associated clinical outcomes. METHODS Available baseline/pre-baseline HRCT scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance and high forced vital capacity: DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with PH-IIP to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
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riociguat for Idiopathic Interstitial Pneumonia associated pulmonary hypertension rise iip a randomised placebo controlled phase 2b study
The Lancet Respiratory Medicine, 2019Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H LeuchteAbstract:Summary Background Idiopathic Interstitial Pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Methods RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and Interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with Idiopathic Interstitial Pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. Findings Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of Interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and Pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52). Interpretation In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP. Funding Bayer AG and Merck & Co.
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exercise pathophysiology and the role of oxygen therapy in Idiopathic Interstitial Pneumonia
Respirology, 2016Co-Authors: Tamera J Corte, Lauren K Troy, Iven H Young, Edmund M T LauAbstract:Exercise limitation is a common feature in Idiopathic Interstitial Pneumonia (IIP). There are multiple contributing pathophysiological mechanisms, including ventilatory mechanical limitation, impaired gas exchange, pulmonary vascular insufficiency and peripheral muscle dysfunction. Progressive exertional dyspnoea and functional incapacity impact significantly on quality of life. Exercise-induced desaturation is frequently observed and is predictive of poorer outcomes. Tests to assess the cardiorespiratory system under stress (e.g. cardiopulmonary exercise testing and the 6-min walk test) can provide important physiologic and prognostic information as adjuncts to resting measurements of lung function. Despite many advances in understanding disease mechanisms, therapies to improve exercise capacity, symptom burden and quality of life are lacking. Exercise training and supplemental oxygen are two potential interventions that require closer evaluation in patients with IIP.
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bosentan in pulmonary hypertension associated with fibrotic Idiopathic Interstitial Pneumonia
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Tamera J Corte, Gregory J Keir, Konstantinos Dimopoulos, Luke Howard, P A Corris, Lisa Parfitt, Claire Foley, Monica Yanezlopez, Daphne Babalis, Philip MarinoAbstract:Rationale: Pulmonary hypertension (PH) associated with fibrotic Idiopathic Interstitial Pneumonia (IIP; Idiopathic pulmonary fibrosis and nonspecific Interstitial Pneumonia) confers important additional morbidity and mortality. Objectives: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist bosentan in this patient group. Methods: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n = 40) or placebo (n = 20). The primary study endpoint was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks. Measurements and Main Results: Sixty patients (42 men; mean age, 66.6 ± 9.2 yr), with a mean pulmonary artery pressure of 36.0 (± 8.9) mm Hg, PVRi 13.0 (± 6.7) Wood Units/m2 and reduced cardiac index of 2.21 (± 0.5) L/min/m2 were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter data were available for analysis in 39 patients (bosentan = 25, placebo = 14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of greater than or equal to 20% (P = 0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group). Conclusions: This study shows no difference in invasive pulmonary hemodynamics, functional capacity, or symptoms between the bosentan and placebo groups over 16 weeks. Our data do not support the use of the dual endothelin-1 receptor antagonist, bosentan, in patients with PH and fibrotic IIP. Clinical trial registered with www.clinicaltrials.gov (NCT 00637065).
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pulmonary function vascular index predicts prognosis in Idiopathic Interstitial Pneumonia
Respirology, 2012Co-Authors: Tamera J Corte, David M Hansell, Elizabeth Renzoni, Stephen J Wort, Peter S Macdonald, Anthony J Edey, Toby M MaherAbstract:Background and objective: Pulmonary hypertension (PH) is associated with increased mortality in fibrotic Idiopathic Interstitial Pneumonia (IIP). We hypothesize that baseline KCO (diffusing capacity of carbon monoxide/alveolar volume) and 6-month decline in KCO reflect PH, thus predicting mortality in IIP. Methods: All IIP referrals (2004–2007) were identified (n = 269). 192 had pulmonary function at 6 months. Fifty-two (27%) died during follow-up (median 22.5 months). Outcome was evaluated for early (1 year from 6-month pulmonary function) and overall mortality. A vascular index best predicting mortality was identified (using baseline and 6-month decline in KCO) and evaluated against PH at echocardiography. Results: Baseline and 6-month decline in KCO were associated with early and overall mortality. A positive vascular index (baseline KCO% ≤ 50% and/or ≥15% decline in KCO at 6 months; n = 40) was strongly predictive of early and overall mortality. Neither a diagnosis of Idiopathic pulmonary fibrosis nor PH predicted early death when incorporated into this model. In patients without baseline PH, with follow-up echocardiography (n = 60), a positive vascular index was associated with PH at follow-up. Conclusions: A vascular index comprised of baseline and 6-month decline in KCO strongly predicted increased mortality and development of PH on echocardiography. In, KCO may be an important marker for pulmonary vascular disease and its associated mortality.
Fernando J. Martinez - One of the best experts on this subject based on the ideXlab platform.
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impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and Idiopathic Interstitial Pneumonia a post hoc subgroup analysis of the rise iip study
Journal of Heart and Lung Transplantation, 2021Co-Authors: Steven D Nathan, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, H Leuchte, Anne M Keogh, Nesrin Mogulkoc, Silvia UlrichAbstract:BACKGROUND RISE-IIP, a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP), was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography (HRCT), and associated clinical outcomes. METHODS Available baseline/pre-baseline HRCT scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance and high forced vital capacity: DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with PH-IIP to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
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riociguat for Idiopathic Interstitial Pneumonia associated pulmonary hypertension rise iip a randomised placebo controlled phase 2b study
The Lancet Respiratory Medicine, 2019Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H LeuchteAbstract:Summary Background Idiopathic Interstitial Pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Methods RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and Interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with Idiopathic Interstitial Pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. Findings Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of Interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and Pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52). Interpretation In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP. Funding Bayer AG and Merck & Co.
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Idiopathic Interstitial Pneumonia associated pulmonary hypertension a target for therapy
Respiratory Medicine, 2017Co-Authors: Steven D Nathan, Harold R Collard, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, Athol U WellsAbstract:Advances in the treatment of Idiopathic Interstitial Pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results.
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comparison of disease progression and mortality of connective tissue disease related Interstitial lung disease and Idiopathic Interstitial Pneumonia
Arthritis Care and Research, 2005Co-Authors: Sosa V Kocheril, Barry H. Gross, Ella A Kazerooni, Kevin R Flaherty, Fernando J. Martinez, Brent E Appleton, Emily C Somers, Leslie J CroffordAbstract:Objective To compare disease progression and mortality between Idiopathic Interstitial Pneumonia (IIP) and Interstitial lung disease (ILD) due to connective tissue diseases (CTD) including scleroderma, rheumatoid arthritis, systemic lupus, polymyositis, dermatomyositis, Sjogren's syndrome, and mixed CTD. Methods A case-control study of patients with CTD-ILD (n = 46) and IIP controls (n = 51), seen at the University of Michigan between July 1,1998 and June 30,1999 and followed until March 30, 2002, was conducted. Survival analysis and Cox regression were performed to estimate survival, accounting for demographic and clinical parameters, including pulmonary function tests and high resolution computed tomography (HRCT) diagnosis and scoring. Results Median followup time was 4.4 person-years. Five-year survival in the IIP group was 51.9% (95% confidence interval [95% CI] 30.8–69.4) versus 43.4% (95% CI 21.1–63.9) in the CTD-ILD group. There were no significant differences among HRCT diagnostic categories between IIP and CTD-ILD. A fibrotic score ≥2 was associated with decreased survival among the entire group. Age at diagnosis and most recent forced vital capacity were significant predictors of mortality when adjusted for IIP versus CTD-ILD diagnosis, sex, and Interstitial score. Conclusion Contrary to expectation, CTD-ILD compared with IIP appears to be associated with a worse prognosis when adjusted for age. A higher fibrotic score is suggestive of decreased survival.
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Human Pulmonary Fibroblasts Exhibit Altered Interleukin-4 and Interleukin-13 Receptor Subunit Expression in Idiopathic Interstitial Pneumonia
The American journal of pathology, 2004Co-Authors: Claudia Jakubzick, Kevin R Flaherty, Galen B Toews, Thomas V Colby, Esther S. Choi, Kristin J. Carpenter, Steven L. Kunkel, Holly L. Evanoff, Fernando J. Martinez, William D TravisAbstract:Abnormal proliferation of pulmonary fibroblasts is a prominent feature of chronic pulmonary fibrotic diseases such as Idiopathic Interstitial Pneumonia (IIP), but it is not presently clear how this proliferative response by lung fibroblasts can be therapeutically modulated. In the present study, we examined whether it was possible to selectively target primary human pulmonary fibroblasts grown out of surgical lung biopsies (SLBs) from IIP patients based on their expression of interleukin-4 receptor (IL-4R) and IL-13R subunits. Pulmonary fibroblast lines cultured from patients with the severest form of IIP, namely usual Interstitial Pneumonia, exhibited the greatest gene and protein expression of IL-4Rα, IL-13Rα1, and IL-13Rα2 compared with primary pulmonary fibroblast lines grown from other IIP SLBs and normal SLBs. When exposed to increasing concentrations of a chimeric protein comprised of human IL-13 and a truncated version of Pseudomonas exotoxin (IL13-PE), the proliferation of primary usual Interstitial Pneumonia fibroblasts was inhibited to a much greater extent compared with fibroblast lines from nonspecific Interstitial Pneumonia and respiratory bronchiolitis/Interstitial lung disease patient groups. Fibroblasts from normal patients exhibited minimal susceptibility to the cytotoxic effect of IL13-PE. IL13-PE-mediated targeting of IIP fibroblasts was dependent on their expression of IL-4Rα and IL-13Rα2. Thus, these data suggest that the abnormal proliferative properties of human lung fibroblasts from certain IIP patient groups can be modulated in a manner that is dependent on the IL-4 and IL-13 receptor subunit expression by these cells.
Steven D Nathan - One of the best experts on this subject based on the ideXlab platform.
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impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and Idiopathic Interstitial Pneumonia a post hoc subgroup analysis of the rise iip study
Journal of Heart and Lung Transplantation, 2021Co-Authors: Steven D Nathan, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, H Leuchte, Anne M Keogh, Nesrin Mogulkoc, Silvia UlrichAbstract:BACKGROUND RISE-IIP, a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP), was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography (HRCT), and associated clinical outcomes. METHODS Available baseline/pre-baseline HRCT scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance and high forced vital capacity: DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with PH-IIP to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
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riociguat for Idiopathic Interstitial Pneumonia associated pulmonary hypertension rise iip a randomised placebo controlled phase 2b study
The Lancet Respiratory Medicine, 2019Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H LeuchteAbstract:Summary Background Idiopathic Interstitial Pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Methods RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and Interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with Idiopathic Interstitial Pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. Findings Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of Interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and Pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52). Interpretation In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP. Funding Bayer AG and Merck & Co.
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Idiopathic Interstitial Pneumonia associated pulmonary hypertension a target for therapy
Respiratory Medicine, 2017Co-Authors: Steven D Nathan, Harold R Collard, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, Athol U WellsAbstract:Advances in the treatment of Idiopathic Interstitial Pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results.
Marius M Hoeper - One of the best experts on this subject based on the ideXlab platform.
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pulmonary hypertension in fibrosing Idiopathic Interstitial Pneumonia uncertainties challenges and opportunities
Journal of Heart and Lung Transplantation, 2021Co-Authors: Reda E Girgis, Marius M HoeperAbstract:Abstract Pulmonary hypertension is a serious complication of chronic fibrosing Idiopathic Interstitial Pneumonia (PH-fIIP) leading to greater morbidity and mortality. The pathophysiologic basis for PH in fIIP is not completely understood, but microvascular rarefaction may play a key role. Severe hypoxemia and reduced diffusion capacity are characteristic. Doppler echocardiography has limited diagnostic utility and right heart catheterization is required to confirm the diagnosis. Lung volumes can be minimally affected, and radiographic findings can be subtle, making the distinction from pulmonary arterial hypertension (PAH) challenging. Several randomized controlled trials of PAH targeted therapies have recently been completed. Endothelin-receptor antagonists have shown either no benefit or harm. Sildenafil may have some favorable short-term effects but does not appear to impact long-term outcomes. Riociguat treatment increased hospitalizations and mortality. A recent trial of inhaled treprostinil demonstrated improved exercise capacity, but the impact on long-term morbidity and mortality are unknown. Currently, the only viable option for improved survival is lung transplantation. Early referral is imperative to optimize post-transplant outcomes.
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impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and Idiopathic Interstitial Pneumonia a post hoc subgroup analysis of the rise iip study
Journal of Heart and Lung Transplantation, 2021Co-Authors: Steven D Nathan, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, H Leuchte, Anne M Keogh, Nesrin Mogulkoc, Silvia UlrichAbstract:BACKGROUND RISE-IIP, a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP), was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography (HRCT), and associated clinical outcomes. METHODS Available baseline/pre-baseline HRCT scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance and high forced vital capacity: DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with PH-IIP to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
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riociguat for Idiopathic Interstitial Pneumonia associated pulmonary hypertension rise iip a randomised placebo controlled phase 2b study
The Lancet Respiratory Medicine, 2019Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H LeuchteAbstract:Summary Background Idiopathic Interstitial Pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Methods RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and Interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with Idiopathic Interstitial Pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. Findings Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of Interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and Pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52). Interpretation In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP. Funding Bayer AG and Merck & Co.
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Idiopathic Interstitial Pneumonia associated pulmonary hypertension a target for therapy
Respiratory Medicine, 2017Co-Authors: Steven D Nathan, Harold R Collard, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, Athol U WellsAbstract:Advances in the treatment of Idiopathic Interstitial Pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results.
H Leuchte - One of the best experts on this subject based on the ideXlab platform.
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impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and Idiopathic Interstitial Pneumonia a post hoc subgroup analysis of the rise iip study
Journal of Heart and Lung Transplantation, 2021Co-Authors: Steven D Nathan, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, H Leuchte, Anne M Keogh, Nesrin Mogulkoc, Silvia UlrichAbstract:BACKGROUND RISE-IIP, a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP), was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography (HRCT), and associated clinical outcomes. METHODS Available baseline/pre-baseline HRCT scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score. RESULTS Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance and high forced vital capacity: DLCO ratio at baseline also appeared to be risk factors for mortality. CONCLUSIONS High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with PH-IIP to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.
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riociguat for Idiopathic Interstitial Pneumonia associated pulmonary hypertension rise iip a randomised placebo controlled phase 2b study
The Lancet Respiratory Medicine, 2019Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H LeuchteAbstract:Summary Background Idiopathic Interstitial Pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with Idiopathic Interstitial Pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Methods RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and Interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18–80 years) diagnosed with Idiopathic Interstitial Pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150–450 m, WHO functional classes II–IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5–2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825. Findings Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6–203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of Interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and Pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI −9 to 52). Interpretation In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk–benefit profile. Riociguat should not be used in patients with PH-IIP. Funding Bayer AG and Merck & Co.
