G Simonneau

Université Paris-Sud 11, Orsay, Île-de-France, France

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Publications (671)4105.59 Total impact

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  • Thorax; 11/2013
  • European Respiratory Journal 11/2013; 43(3). DOI:10.1183/09031936.00151313 · 7.13 Impact Factor
  • Thorax; 11/2013
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    European Respiratory Journal 10/2013; 43(2). DOI:10.1183/09031936.00147013 · 7.13 Impact Factor
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    ABSTRACT: Pulmonary hypertension (PH) is a progressive disorder characterized by an increase in pulmonary artery pressure and structural changes in the pulmonary vasculature. Several observations indicate that growth factors play a key role in PH by modulating pulmonary artery smooth muscle cell (PA-SMC) function. In rats, established monocrotaline-induced PH (MCT-PH) can be reversed by blocking platelet-derived growth factor receptors (PDGF-R), epidermal growth factor receptors (EGF-R), or fibroblast growth factor receptors (FGF-R). All these receptors belong to the receptor tyrosine kinase (RTK) family. We evaluated whether RTK blockade by the nonspecific growth factor inhibitor, suramin, reversed advanced MCT-PH in rats via its effects on growth-factor signaling pathways. We found that suramin inhibited RTK and ERK1/2 phosphorylation in cultured human PA-SMCs. Suramin inhibited PA-SMC proliferation induced by serum, PDGF, FGF2, or EGF in vitro and ex vivo. Treatment with suramin from day 1 to day 21 after monocrotaline injection attenuated PH development, as shown by lower values for pulmonary artery pressure, right ventricular hypertrophy, and distal vessel muscularization on day 21 compared to control rats. Treatment with suramin from day 21 to day 42 after monocrotaline injection reversed established PH, thereby normalizing the pulmonary artery pressure values and vessel structure. Suramin treatment suppressed PA-SMC proliferation and attenuated both the inflammatory response and the deposition of collagen. RTK blockade by suramin can prevent MCT-PH and reverse established MCT-PH in rats. This study suggests that an anti-RTK strategy that targets multiple RTKs could be useful in the treatment of pulmonary hypertension.
    PLoS ONE 10/2013; 8(10):e77073. DOI:10.1371/journal.pone.0077073 · 3.53 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of small pulmonary arteries that leads to elevated pulmonary arterial pressure and right heart failure. During the last decades, an improved understanding of the pathophysiology of the disease has resulted in the development of effective therapies targeting endothelial dysfunction (epoprostenol and derivatives, endothelin receptor antagonists and phosphodiesterase type 5 inhibitors). These drugs allow clinical, functional and hemodynamic improvement, but to date, no cure exists for PAH and prognosis remains poor. Recently, several additional pathways have been suggested to be involved in the pathogenesis of PAH, and may represent innovative therapies. In this summary, we review conventional therapy, pharmacological agents currently available for the treatment of PAH and the benefit/risk ratio of potential future therapies.
    Clinical Pharmacology &#38 Therapeutics 10/2013; DOI:10.1016/j.pharmthera.2013.10.002 · 7.39 Impact Factor
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    ABSTRACT: Late-Breaking AbstractsSESSION TYPE: Original Investigation SlidePRESENTED ON: Tuesday, October 29, 2013 at 04:30 PM - 05:30 PMPURPOSE: In the 16-week Phase III CHEST-1 study, riociguat, a novel soluble guanylate cyclase stimulator, significantly improved 6-minute walking distance (6MWD) and a range of secondary endpoints in patients with CTEPH. These improvements were maintained for a further 12 weeks in the CHEST-2 long-term extension study. Here we present 1-year data from CHEST-2.METHODS: Patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension (PH) after pulmonary endarterectomy could enter CHEST-2 after successfully completing CHEST-1 without ongoing riociguat-related serious adverse events. During the initial 8-week blinded titration period of CHEST-2, patients in the riociguat arm continued on their optimum dose (up to 2.5 mg tid) while receiving sham titration; patients in the placebo arm were titrated to their optimum dose of riociguat (up to 2.5 mg tid). The primary endpoints were safety and tolerability; secondary endpoints included change in 6MWD and WHO functional class (FC).RESULTS: Of 261 patients enrolled in CHEST-1, 237 (91%) entered CHEST-2. In this interim analysis (cut-off March 2013), 211 (89%) patients were ongoing and 179 (76%) had received ≥1 year of treatment. Riociguat was well tolerated, with 3% of patients withdrawing due to adverse events. At the end of CHEST-1, mean±SD 6MWD had increased by 50±59 m in the riociguat arm and 8±63 m in the placebo arm of the cohort entering CHEST-2. After 1 year of CHEST-2 (overall population; n=172), 6MWD had increased by 51±62 m versus CHEST-1 baseline. At the end of CHEST-1, FC was improved/stable/worsened in 35/62/3% of riociguat patients and 16/81/2% of placebo patients; after 1 year of CHEST-2 (overall population; n=178), the proportions were 46/49/3% (data missing for two patients) versus CHEST-1 baseline. Twenty-two (9%) patients received additional PH medication during CHEST-2 (n=19 due to worsening PH).CONCLUSIONS: Riociguat has a good long-term safety profile and is the first therapy to show sustained benefits in 6MWD and FC in patients with CTEPH.CLINICAL IMPLICATIONS: Riociguat is a promising option for the long-term treatment of patients with inoperable CTEPH.DISCLOSURE: Gérald Simonneau: Grant monies (from industry related sources): Gerald Simonneau has received grant money paid to his institution from Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Gerald Simonneau has received consulting fees, honorarium and/or support for travel to meetings from Bayer, Other: Gerald Simonneau has received fees for participation in review activities from Bayer Andrea D'Armini: Other: Andrea D'Armini received fees for participation in review activities from Bayer Hossein Ghofrani: Grant monies (from industry related sources): Hossein-Ardeschir Ghofrani has received grant money paid to his institution by Bayer HealthCare, Consultant fee, speaker bureau, advisory committee, etc.: Hossein-Ardeschir Ghofrani has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare Friedrich Grimminger: Grant monies (from industry related sources): Friedrich Grimminger has received grant money paid to his institution by Bayer HealthCare, Consultant fee, speaker bureau, advisory committee, etc.: Friedrich Grimminger has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare Marius Hoeper: Grant monies (from industry related sources): Marius M. Hoeper has received grant money paid to his institution by Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Marius M. Hoeper has received consulting fees, honorarium and/or support for travel from Bayer Pavel Jansa: Consultant fee, speaker bureau, advisory committee, etc.: Pavel Jansa has received consulting fees, honorarium and/or support for travel to meetings from Bayer, Other: Pavel Jansa has received fees for participation in review activities from Bayer Nick Kim: Consultant fee, speaker bureau, advisory committee, etc.: Nick H. Kim has received consulting fees, honorarium and/or support for travel to meetings from Bayer Martin Wilkins: Grant monies (from industry related sources): Martin R. Wilkins has received a grant paid to his institution from Bayer HealthCare, Consultant fee, speaker bureau, advisory committee, etc.: Martin R. Wilkins has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare, Other: Martin R. Wilkins has received fees for participation in review activities from Bayer HealthCare Arno Fritsch: Shareholder: Arno Fritsch has received stock/stock options from Bayer HealthCare, Employee: Arno Fritsch is a full-time employee of Bayer HealthCare Neil Davie: Employee: Neil Davie is a full-time employee of Bayer HealthCare Gerrit Weimann: Employee: Gerrit Weimann is a full-time employee of Bayer HealthCare Eckhard Mayer: Consultant fee, speaker bureau, advisory committee, etc.: Eckhard Mayer has received consulting fees, honorarium and/or support for travel to meetings from Bayer, Other: Eckhard Mayer has received fees for participation in review activities from Bayer The following authors have nothing to disclose: Chen WangRiociguat is an investigational new drug currently in process for registration submission to health authorities, after successful finalisation of a RCT in patients with PAH.
    Chest 10/2013; 144(4_MeetingAbstracts):1023A. DOI:10.1378/chest.1783236 · 7.13 Impact Factor
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    ABSTRACT: Pulmonary HypertensionSESSION TYPE: Original Investigation SlidePRESENTED ON: Monday, October 28, 2013 at 01:45 PM - 03:15 PMPURPOSE: In SERAPHIN, a randomized, controlled trial (NCT00660179) in pulmonary arterial hypertension (PAH), macitentan significantly reduced the risk of morbidity and mortality (primary endpoint) and death due to PAH or hospitalization for PAH (DHPAH; secondary endpoint). This subanalysis examined the effects of macitentan on long-term outcomes in incident and prevalent patients not receiving background PAH-specific therapy (treatment-naïve patients).METHODS: 742 PAH patients (≥12 years) were randomized to placebo, 3 mg or 10 mg macitentan, once daily. According to the delay between PAH diagnosis and inclusion into the study, treatment-naïve patients were classified as incident (≤6 months) or prevalent (>6 months). Unadjusted hazard ratios (HR; 95% confidence intervals) were calculated using Cox regression models to determine the treatment effect of macitentan on morbidity and mortality and DHPAH.RESULTS: Of 265 treatment-naïve patients, 108 were incident and 157 were prevalent patients; median time from PAH diagnosis to study inclusion was 50 and 834 days, respectively. At baseline for incident and prevalent patients, median 6-minute walk distance was 357 and 370 m, cardiac index was 2.37 and 2.45 L/min/m2 and pulmonary vascular resistance was 780 and 733 dyn.sec/cm5 respectively. A morbidity/mortality event occurred in 63.9, 40.0 and 38.2% of incident patients and 42.4, 28.9 and 24.5% of prevalent patients on placebo, macitentan 3 mg and 10 mg, respectively. For morbidity and mortality, the HR for macitentan 3 mg and 10 mg, respectively, were 0.38 (0.20-0.73) and 0.40 (0.20-0.79) in incident patients and 0.60 (0.31-1.17) and 0.47 (0.24-0.91) in prevalent patients. For DHPAH, the HR for macitentan 3 mg and 10 mg, respectively, for incident patients were 0.45 (0.23-0.91) and 0.22 (0.09-0.57) and for prevalent patients were 0.49 (0.20-1.18) and 0.38 (0.16-0.92).CONCLUSIONS: Incident and prevalent PAH patients had similar baseline disease severity, yet the natural history of incident patients (placebo arm) show a higher risk of morbidity and mortality. Despite their poor prognosis, macitentan significantly reduced the risk of morbidity and mortality in both incident and prevalent PAH patients.CLINICAL IMPLICATIONS: Macitentan is an effective first-line therapy for improving long-term outcomes in both newly diagnosed and prevalent PAH patients.DISCLOSURE: Gérald Simonneau: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Novartis, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Pfizer Marion Delcroix: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline Nazzareno Galiè: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Bayer Hossein Ghofrani: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Merck, Consultant fee, speaker bureau, advisory committee, etc.: Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Ergonex, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): Ergonex, Grant monies (from industry related sources): Pfizer Pavel Jansa: Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: AOP Orphan, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Grant monies (from industry related sources): Actelion Franck - Olivier Le Brun: Employee: Actelion, Shareholder: Actelion Sanjay Mehta: Grant monies (from industry related sources): Heart & Stroke Foundation of Ontario/Canada (HSFO/C), Grant monies (from industry related sources): Canadian Institute of Health Research / CIHR, Grant monies (from industry related sources): Ontario Thoracic Society (OTS) Loic Perchenet: Employee: Actelion Pharmaceuticals Ltd, Shareholder: Actelion Pharmaceuticals Ltd Tomas Pulido: Grant monies (from industry related sources): National Heart Institute, Consultant fee, speaker bureau, advisory committee, etc.: Actelion B. Sastry: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKine Olivier Sitbon: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Bayer Rogério Souza: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Ely Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline Adam Torbicki: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Ely Lilly, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): Actelion , Grant monies (from industry related sources): United Therapeutics, Grant monies (from industry related sources): AOP Orphan Pharmaceutics, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Bristol Myers Squibb, Grant monies (from industry related sources): Sanofi Aventis Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Lung LLC, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: Aires, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GeNo The following authors have nothing to disclose: Richard ChannickMacitentan is currently under regulatory review as a treatment for pulmonary arterial hypertension.
    Chest 10/2013; 144(4_MeetingAbstracts):876A. DOI:10.1378/chest.1701395 · 7.13 Impact Factor
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    ABSTRACT: Pulmonary HypertensionSESSION TYPE: Original Investigation SlidePRESENTED ON: Monday, October 28, 2013 at 01:45 PM - 03:15 PMPURPOSE: In SERAPHIN (NCT00660179), macitentan significantly reduced the risk of morbidity and mortality in patients with pulmonary arterial hypertension (PAH). This analysis explored the association of short-term changes in WHO functional class (FC) with the long-term outcome of death due to PAH or hospitalization for PAH (DHPAH).METHODS: 742 PAH patients (≥12 years) were randomized to placebo, 3 mg or 10 mg macitentan, once daily. Hazard ratios (HR; 95% confidence interval), both unadjusted and adjusted for significant baseline covariates, were calculated using Cox proportional hazard models, to measure the association between DHPAH and A) patients in FC II at baseline who, at Month 6, remained in FC II versus those who worsened to FC III/IV or improved to FC I; B) patients in FC III at baseline who, at Month 6, remained in FC III versus those who worsened to FC IV or improved to FC I/II. These analyses were performed independently of treatment in patients with available data for FC at Month 6 and from Month 6 up to end of treatment for DHPAH.RESULTS: At baseline, 387 patients were in FC II and 337 in FC III. The proportion of DHPAH events in patients in FC II at baseline who, at Month 6, remained in FC II was 15.8%, worsened to FC III/IV was 29.2% and improved to FC I was 14.3%; HR for the risk of DHPAH events in patients who worsened or improved from FC II at baseline against unchanged were 3.71 (1.67-8.25; P=0.001) and 0.85 (0.34-2.15; P=0.74). The proportion of DHPAH events in patients in FC III at baseline who, at Month 6, remained in FC III was 30.8%, worsened to FC IV was 37.5% and improved to FC I/II was 23.3%; HR for the risk of DHPAH events in patients who worsened or improved from FC III at baseline against unchanged were 5.16 (1.57-17.0; P=0.007) and 0.66 (0.39-1.11; P=0.116). Data were similar when analyses were adjusted for significant baseline covariates.CONCLUSIONS: Deterioration in FC over a 6-month period was significantly associated with a higher risk of DHPAH. For patients in FC III at baseline, improvement to FC I/II over 6 months was associated with a non-significant reduction in risk of DHPAH compared with those who remained in FC III.CLINICAL IMPLICATIONS: Short-term worsening in FC is clearly associated with a worse long-term prognosis, while improving to FC II over the short term, might be associated with improved long-term prognosis.DISCLOSURE: Rogério Souza: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Ely Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline Richard Channick: Grant monies (from industry related sources): Actelion Marion Delcroix: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline Nazzareno Galiè: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Bayer Hossein Ghofrani: Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Merck, Consultant fee, speaker bureau, advisory committee, etc.: Novartis, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: Ergonex, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): Ergonex, Grant monies (from industry related sources): Pfizer Pavel Jansa: Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: AOP Orphan, Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Grant monies (from industry related sources): Actelion Franck - Olivier Le Brun: Employee: Actelion, Shareholder: Actelion Sanjay Mehta: Grant monies (from industry related sources): Heart & Stroke Foundation of Ontario/Canada (HSFO/C), Grant monies (from industry related sources): Canadian Institute of Health Research / CIHR, Grant monies (from industry related sources): Ontario Thoracic Society (OTS) Loic Perchenet: Employee: Actelion Pharmaceuticals Ltd, Shareholder: Actelion Pharmaceuticals Ltd Tomas Pulido: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): United Therapuetics B. Sastry: Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline Olivier Sitbon: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): Bayer Adam Torbicki: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Ely Lilly, Grant monies (from industry related sources): Bayer, Grant monies (from industry related sources): Actelion , Grant monies (from industry related sources): United Therapeutics, Grant monies (from industry related sources): AOP Orphan Pharmaceutics, Grant monies (from industry related sources): Pfizer, Grant monies (from industry related sources): Bristol Myers Squibb, Grant monies (from industry related sources): Sanofi Aventis Lewis Rubin: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Lung LLC, Consultant fee, speaker bureau, advisory committee, etc.: Gilead, Consultant fee, speaker bureau, advisory committee, etc.: Aires, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Bayer, Consultant fee, speaker bureau, advisory committee, etc.: GeNo Gérald Simonneau: Consultant fee, speaker bureau, advisory committee, etc.: Actelion, Consultant fee, speaker bureau, advisory committee, etc.: GlaxoSmithKline, Consultant fee, speaker bureau, advisory committee, etc.: Eli Lilly, Consultant fee, speaker bureau, advisory committee, etc.: Pfizer, Consultant fee, speaker bureau, advisory committee, etc.: United Therapeutics, Consultant fee, speaker bureau, advisory committee, etc.: Novartis, Grant monies (from industry related sources): Actelion, Grant monies (from industry related sources): GlaxoSmithKline, Grant monies (from industry related sources): Eli Lilly, Grant monies (from industry related sources): PfizerMacitentan is currently under regulatory review as a treatment for pulmonary arterial hypertension.
    Chest 10/2013; 144(4_MeetingAbstracts):879A. DOI:10.1378/chest.1701714 · 7.13 Impact Factor
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    ABSTRACT: DVT/PE/Pulmonary Hypertension PostersSESSION TYPE: Original InvestigationPRESENTED ON: Wednesday, October 30, 2013 at 01:30 PM - 02:30 PMPURPOSE: In the SERAPHIN trial (NCT00660179), macitentan significantly reduced the risk of morbidity and mortality (primary endpoint) in pulmonary arterial hypertension (PAH) patients. This analysis evaluated the predictive value of N-terminal pro-B natriuretic peptide (NT-pro-BNP), cardiac index (CI) and pulmonary vascular resistance (PVR) on this outcome.METHODS: 742 PAH patients (≥12 years) were randomized to placebo, 3 mg or 10 mg macitentan, once daily. Hazard ratios (HR; 95% confidence intervals) were calculated to measure the association between the risk of morbidity and mortality and interquartile ranges (lowest=Q1 and highest=Q4) of NT-pro-BNP (n=495), CI (n=145) and PVR (n=145) at baseline, absolute values at Month 6, and change from baseline at Month 6. Univariate models and regression models unadjusted or adjusted for significant covariates were used, independently of treatment group. Analyses were performed in patients with available data for NT-pro-BNP, CI and PVR at Month 6, and from Month 6 up to end of treatment for morbidity and mortality.RESULTS: Median baseline and Month 6 values for the placebo, 3 mg and 10 mg macitentan groups for NT-pro-BNP were 716 and 794 fmol/L (n=160), 841 and 759 fmol/L (n=165) and 807 and 707 fmol/L (n=170), respectively; for CI were 2.51 and 2.28 L/min/m2 (n=50), 2.23 and 2.70 L/min/m2 (n=47) and 2.56 and 3.06 L/min/m2 (n=48), respectively; and for PVR were 800 and 907 dyn.sec/cm5 (n=50), 785 and 600 dyn.sec/cm5 (n=47) and 789 and 536 dyn.sec/cm5 (n=48), respectively. The unadjusted HR for baseline NT-pro-BNP Q1 <517 fmol/L vs Q4 >1362 fmol/L was 6.25 (3.58-10.91), for CI Q1 <1.85 L/min/m2 vs Q4 >2.81 L/min/m2 was 2.62 (1.84-3.72) and for PVR Q1 <522 dyn.sec/cm5 vs Q4 >1314 dyn.sec/cm5 was 3.17 (2.14-4.70). Similarly, higher Month 6 absolute values for NT-pro-BNP and PVR, and lower Month 6 absolute values for CI were associated with significant increased risk in morbidity and mortality. Data were similar for both analyses when adjusted for covariates. There was no consistent association between change from baseline to Month 6 and risk of morbidity and mortality.CONCLUSIONS: Higher NT-pro-BNP and PVR, and lower CI values at baseline and at Month 6 were significantly associated with a higher risk of morbidity and mortality, but changes from baseline were not.CLINICAL IMPLICATIONS: Baseline and absolute values at Month 6 for NT-pro-BNP, CI and PVR are valuable cardiac function predictors of long-term outcome in PAH.DISCLOSURE: Richard Channick; grant monies, Actelion. Marion Delcroix; consultant fee, speaker bureau, advisory committee, Actelion, GlaxoSmithKline, Pfizer, United Therapeutics, Bayer, grant monies, Actelion and GlaxoSmithKline. Nazzareno Galie; consultant fee, speaker bureau, advisory committee, grant monies Actelion, Pfizer, GlaxoSmithKline, Eli Lilly, Bayer. Hossein Ghofrani; consultant fee, speaker bureau, advisory committee, grant monies, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer, Bayer, Ergonex, Actelion. Pavel Jansa; consultant free, speaker bureau, advisory committee, United Therapeutics, AOP Orphan, Actelion, grant monies, Actelion. Franck-Olivier LeBrun: Employee, Actelion. Sanjay Mehta: grant monies, Heart & Stroke Foundation of Ontario/Canada, Canadian Institute of Health Research, Ontario Thoracic Society. Loic Perchenet: Employee, Actelion. Tomas Pulido: consultant fee, speaker bureau, advisory committee, Actelion, Pfizer, Eli Lilly, Bayer, grant monies Bayer, Actelion, United Therapeutics. B Sastry; consultant fee, speaker bureau, advisory committee, GlaxoSmithKline. Olivier Sitbon; consultant fee, speaker bureau, advisory committee, Actelion, GlaxoSmith Kline, Pfizer, Eli Lilly, United Therapeutics, grant monies, Actelion, GlaxoSmithKline, Pfizer, Eli Lilly, Bayer. Rogerio Souza; consultant fee, speaker bureau, advisory committee, Actelion, Eli Lilly, Bayer, GlaxoSmith Kline. Adam Torbicki; consultant fee, speaker bureau, advisory committee, Actelion, Eli Lilly, grant monies, Actelion, United Therapeutics, AOP Orphan Pharmaceutics, Pfizer, Bristol Myers Squibb, Sanofi Aventis. Lewis Rubin, consultant fee, speaker bureau, advisory committee, Actelion, Pfizer, United Therapeutics, Lung LLC, Gilead, Aires, GlaxoSmithKline, Bayer, GeNo. Gerald Simmonneau; consultant fee, speaker bureau, advisory committee, Actelion, GlaxoSmithKline, Eli Lilly, Pfizer, United Therapeutics, grant monies, Movartis, Actlion, GlaxoSmithKline, Eli Lilly, Pfizer.
    Chest 10/2013; 144(4_MeetingAbstracts):870B. DOI:10.1378/chest.1701644 · 7.13 Impact Factor
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    American Journal of Respiratory and Critical Care Medicine 09/2013; 188(6):756-9. DOI:10.1164/rccm.201303-0467LE · 11.99 Impact Factor
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    ABSTRACT: Introduction: Sildenafil citrate is a potent, selective phosphodiesterase type 5 inhibitor approved for the treatment of pulmonary arterial hypertension (PAH) and plays an important role in the management of the disease. Areas covered: In this review, we focus on the current available information on the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of sildenafil citrate in PAH through a MEDLINE literature search. Comparison of sildenafil citrate with tadalafil, another phosphodiesterase type 5 inhibitor was also performed. Expert opinion: In the last few years, considerable progress has been made in the understanding and treatment of PAH. Sildenafil citrate has multiple advantages and whether it is first-line treatment alone or in combination for the mild form of the disease, it is one of the treatments of choice. In terms of its future use, more studies are still needed to better evaluate the benefit/risk balance of sildenafil citrate in pediatric populations.
    Expert Opinion on Drug Metabolism &amp Toxicology 09/2013; 9(9):1193-205. DOI:10.1517/17425255.2013.804063 · 2.93 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH.
    European Respiratory Review 09/2013; 22(129):244-50. DOI:10.1183/09059180.00003313
  • Andrei Seferian, Gérald Simonneau
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a progressive disease characterised by remodelling of small pulmonary arteries leading to an increased pulmonary vascular resistance, right ventricular failure and death. Available treatments try to re-establish the equilibrium on three signalling pathways: the prostacyclin, the endothelin (ET)-1 and the nitric oxide. Prostanoids, such as epoprostenol or treprostinil have a vasodilator, antiproliferative and immunomodulatory effect and, despite the administration inconveniences, represent established therapies for severe cases of PAH. Recently oral prostacyclin receptor agonists have shown encouraging results. Many clinical studies targeting the vasoconstrictor ET-1 pathway with receptor antagonists like bosentan and ambrisentan have shown strong results, even more optimism coming from macitentan, the newest drug. Sildenafil and tadalafil, two phosphodiesterase type-5 inhibitors, have shown improved exercise capacity by increasing the nitric oxide level. Riociguat, acting on the same nitric oxide pathway, as a guanylatecyclase activator, has shown promising results in clinical trials and will be available soon. Long-awaited results for tyrosin-kinase inhibitor, imatinib, as an antiproliferative therapy in PAH have been disappointing, due to severe adverse events. In conclusion, although it remains a disease with severe prognosis, the past 20 years have represented a huge progress in terms of treatments for PAH with interesting opportunities for the future.
    European Respiratory Review 09/2013; 22(129):217-26. DOI:10.1183/09059180.00001713
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    ABSTRACT: BACKGROUND Current therapies for pulmonary arterial hypertension have been adopted on the basis of short-term trials with exercise capacity as the primary end point. We assessed the efficacy of macitentan, a new dual endothelin-receptor antagonist, using a primary end point of morbidity and mortality in a long-term trial. METHODS We randomly assigned patients with symptomatic pulmonary arterial hypertension to receive placebo once daily, macitentan at a once-daily dose of 3 mg, or macitentan at a once-daily dose of 10 mg. Stable use of oral or inhaled therapy for pulmonary arterial hypertension, other than endothelin-receptor antagonists, was allowed at study entry. The primary end point was the time from the initiation of treatment to the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. RESULTS A total of 250 patients were randomly assigned to placebo, 250 to the 3-mg macitentan dose, and 242 to the 10-mg macitentan dose. The primary end point occurred in 46.4%, 38.0%, and 31.4% of the patients in these groups, respectively. The hazard ratio for the 3-mg macitentan dose as compared with placebo was 0.70 (97.5% confidence interval [CI], 0.52 to 0.96; P = 0.01), and the hazard ratio for the 10-mg macitentan dose as compared with placebo was 0.55 (97.5% CI, 0.39 to 0.76; P<0.001). Worsening of pulmonary arterial hypertension was the most frequent primary end-point event. The effect of macitentan on this end point was observed regardless of whether the patient was receiving therapy for pulmonary arterial hypertension at baseline. Adverse events more frequently associated with macitentan than with placebo were headache, nasopharyngitis, and anemia. CONCLUSIONS Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. (Funded by Actelion Pharmaceuticals; SERAPHIN ClinicalTrials.gov number, NCT00660179.)
    New England Journal of Medicine 08/2013; 369(9):809-18. DOI:10.1056/NEJMoa1213917 · 54.42 Impact Factor
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    ABSTRACT: Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)
    New England Journal of Medicine 07/2013; 369(4):319-29. DOI:10.1056/NEJMoa1209657 · 54.42 Impact Factor
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    ABSTRACT: Pulmonary arterial hypertension (PAH) is a chronic and progressive disease leading to right heart failure and ultimately death if untreated. The first classification of PH was proposed in 1973. In 2008, the fourth World Symposium on PH held in Dana Point (California, USA) revised previous classifications. Currently, PH is devided into five subgroups. Group 1 includes patients suffering from idiopathic or familial PAH with or without germline mutations. Patients with a diagnosis of PAH should systematically been screened regarding to underlying mutations of BMPR2 gene (bone morphogenetic protein receptor type 2) or more rarely of ACVRL1 (activine receptor-like kinase type 1), ENG (endogline) or Smad8 genes. Pulmonary veno occusive disease and pulmonary capillary hemagiomatosis are individualized and designated as clinical group 1'. Group 2 'Pulmonary hypertension due to left heart diseases' is divided into three sub-groups: systolic dysfonction, diastolic dysfonction and valvular dysfonction. Group 3 'Pulmonary hypertension due to respiratory diseases' includes a heterogenous subgroup of respiratory diseases like PH due to pulmonary fibrosis, COPD, lung emphysema or interstitial lung disease for exemple. Group 4 includes chronic thromboembolic pulmonary hypertension without any distinction of proximal or distal forms. Group 5 regroup PH patients with unclear multifactorial mechanisms. Invasive hemodynamic assessment with right heart catheterization is requested to confirm the definite diagnosis of PH showing a resting mean pulmonary artery pressure (mPAP) of [greater than or equal to]25 mmHg and a normal pulmonary capillary wedge pressure (PCWP) of [less than or equal to]15 mmHg. The assessment of PCWP may allow the distinction between pre-capillary and post-capillary PH (PCWP [greater than or equal to] 15 mmHg). Echocardiography is an important tool in the management of patients with underlying suspicion of PH. The European Society of Cardiology and the European Respiratory Society (ESC-ERS) guidelines specify its role, essentially in the screening proposing criteria for estimating the presence of PH mainly based on tricuspid regurgitation peak velocity and systolic artery pressure (sPAP). The therapy of PAH consists of non-specific drugs including oral anticoagulation and diuretics as well as PAH specific therapy. Diuretics are one of the most important treatment in the setting of PH because right heart failure leads to fluid retention, hepatic congestion, ascites and peripheral edema. Current recommendations propose oral anticoagulation aiming for targeting an International Normalized Ratio (INR) between 1.5-2.5. Target INR for patients displaying chronic thromboembolic PH is between 2--3. Better understanding in pathophysiological mechanisms of PH over the past quarter of a century has led to the development of medical therapeutics, even though no cure for PAH exists. Several specific therapeutic agents were developed for the medical management of PAH including prostanoids (epoprostenol, trepoprostenil, iloprost), endothelin receptor antagonists (bosentan, ambrisentan, macitentan soon available) and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil). This review discusses the current state of art regarding to epidemiologic aspects of PH, diagnostic approaches and the current classification of PH. In addition, currently available specific PAH therapy is discussed as well as future treatments.
    Orphanet Journal of Rare Diseases 07/2013; 8(1):97. DOI:10.1186/1750-1172-8-97 · 3.96 Impact Factor

Publication Stats

33k Citations
4,105.59 Total Impact Points

Institutions

  • 1998–2015
    • Université Paris-Sud 11
      • • Faculté de Médecine
      • • Service de Pneumologie
      Orsay, Île-de-France, France
  • 1990–2015
    • Centre Chirurgical Marie Lannelongue
      Plessis-Robinson, Île-de-France, France
  • 2013–2014
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France
    • Mater Misericordiae University Hospital
      • Department of Respiratory Medicine
      Dublin, Leinster, Ireland
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
    • Vitos Gießen-Marburg
      Gieben, Hesse, Germany
  • 2001–2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Arkansas Children's Hospital
      Little Rock, Arkansas, United States
  • 1988–2013
    • Hôpital Antoine-Béclère – Hôpitaux universitaires Paris-Sud
      Clamart, Île-de-France, France
  • 2002–2012
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Harvard University
      Cambridge, Massachusetts, United States
    • Universitätsklinikum Jena
      Jena, Thuringia, Germany
  • 2010
    • Université Libre de Bruxelles
      Bruxelles, Brussels Capital Region, Belgium
  • 2005–2010
    • University of Bologna
      • Institute of Cardiology
      Bologna, Emilia-Romagna, Italy
    • University of California, San Francisco
      San Francisco, California, United States
    • Université Paris 13 Nord
      Île-de-France, France
    • University of Washington Seattle
      Seattle, Washington, United States
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
    • Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval)
      Québec, Quebec, Canada
  • 2004–2010
    • University of California, San Diego
      • Division of Pulmonary and Critical Care Medicine
      San Diego, California, United States
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2009
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Lutetia Parisorum, Île-de-France, France
    • Centre Hospitalier Universitaire de Brest
      Brest, Brittany, France
    • Palmelit Francia
      Montferrier, Languedoc-Roussillon, France
  • 2007
    • Columbia University
      New York, New York, United States
  • 2006
    • University of Glasgow
      Glasgow, Scotland, United Kingdom
    • Polytech Paris-UPMC
      Lutetia Parisorum, Île-de-France, France
  • 2002–2006
    • Hannover Medical School
      Hanover, Lower Saxony, Germany
  • 1986–2006
    • Hôpital Henri Mondor (Hôpitaux Universitaires Henri Mondor)
      Créteil, Île-de-France, France
  • 1997
    • Azienda Ospedaliera Niguarda Ca' Granda
      • Department of Pneumology
      Milano, Lombardy, Italy
  • 1991–1994
    • University of Tours
      Tours, Centre, France
  • 1981
    • Johns Hopkins Medicine
      • Department of Anesthesiology and Critical Care Medicine
      Baltimore, Maryland, United States