[Show abstract][Hide abstract] ABSTRACT: Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated.Data from newly diagnosed NYHA FC III/IV PAH patients (n = 19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry.Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean±sd 32±19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively.This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.
Full-text · Article · Mar 2014 · European Respiratory Journal
[Show abstract][Hide abstract] ABSTRACT: Background
The double-blind phase of the EARLY study of bosentan remains the only randomized controlled trial of a PAH-targeted therapy in World Health Organization functional class (FC) II patients. We report on the efficacy, safety, disease worsening, survival and prognostic factors in mildly symptomatic pulmonary arterial hypertension (PAH) patients treated with bosentan in the open-label extension phase of the EARLY study.
Exploratory efficacy outcomes included 6-minute walk distance (6MWD) and WHO FC. Adverse events were recorded. Kaplan–Meier analysis was used to estimate time to first PAH worsening event (death, initiation of intravenous or subcutaneous prostanoids, atrial septostomy or lung transplantation) and survival. Cox regression analysis determined factors prognostic of survival.
Median exposure to bosentan (n = 173) was 51 months. At the end of the bosentan-treatment assessment period, 77.8% of patients were in WHO FC I/II. Adverse events led to discontinuation of bosentan in 20.2% of patients. Aminotransferase elevations > 3 x upper limit of normal occurred in 16.8%. Four-year PAH-event-free survival and survival were 79.5% (95% confidence intervals [95% CI] 73.4, 85.6) and 84.8% [95% CI 79.4, 90.2], respectively. Low 6MWD, low mixed venous oxygenation, high N-terminal pro hormone of brain natriuretic peptide levels and PAH associated with connective tissue disease were associated with a higher risk of death.
The majority of patients exposed to long-term bosentan maintained or improved their functional class. Approximately 20% of the patients discontinued treatment because of adverse events, which were most commonly PAH worsening and elevated liver enzymes.
Full-text · Article · Mar 2014 · International journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: DVT/PE/Pulmonary HypertensionSESSION TYPE: Slide PresentationsPRESENTED ON: Sunday, March 23, 2014 at 12:15 PM - 01:15 PMPURPOSE: The long-term effect of riociguat was compared in patients with CTEPH in FC I/II versus FC III/IV at CHEST-1 baseline.
In CHEST-1, patients were randomized to riociguat individual-dose titration (up to 2.5 mg tid) or placebo. Patients could enter CHEST-2 after completing CHEST-1 without ongoing riociguat-related SAEs; placebo patients were titrated to their optimum riociguat dose (up to 2.5 mg tid) and riociguat patients continued on their optimum dose.
91% of CHEST-1 patients (n=237) entered CHEST-2. Of these, 211 (89%) were ongoing in this interim analysis (cut-off March 2013; mean treatment duration 582 days); the numbers of patients in FC I/II/III/IV at CHEST-1 baseline were 3/73/154/6. At CHEST-1 completion, mean±SD 6MWD in the FC I/II subgroup increased by 56±65 m and 20±51 m in riociguat and placebo patients, respectively, versus 47±55 m and 2±68 m in the FC III/IV subgroup. After 12 weeks of CHEST-2, 6MWD in the FC I/II subgroup increased by 70±55 m and 41±61 m in ex-riociguat and ex-placebo patients, versus 51±74 m and 45±78 m in the FC III/IV subgroup. In all patients at 1 year, 6MWD increased by 51±52 m in the FC I/II subgroup (n=61) and 52±68 m in the FC III/IV subgroup (n=110). At CHEST-1 completion in the FC I/II subgroup, FC improved/stablilized/worsened in 16/76/8% and 12/84/4% of riociguat and placebo patients; proportions in the FC III/IV subgroup were 44/55/1% and 18/80/2%, respectively. In all patients at 1 year, proportions were 25/67/8% in the FC I/II subgroup (n=63) and 58/40/1% in the FC III/IV subgroup (n=114; data missing for n=1). At the cut-off, 7 (9%) patients in the FC I/II subgroup had experienced clinical worsening and 4 (5%) had died, versus 31 (19%) and 9 (6%), respectively, in the FC III/IV subgroup.
Riociguat increased 6MWD and improved/stabilized FC in most patients in FC I/II and FC III/IV.
Long-term riociguat appears to show benefit in persistent/recurrent and inoperable CTEPH patients in both WHO FC I/II and WHO FC III/IV.
Andrea M D'Armini: Other Andrea D'Armini received fees for participation in review activities from Bayer: Hossein-Ardeschir Ghofrani: Grant monies (from industry related sources) Hossein-Ardeschir Ghofrani has received grant money paid to his institution by Bayer HealthCare: Friedrich Grimminger: Grant monies (from industry related sources) Friedrich Grimminger has received grant money paid to his institution by Bayer HealthCare: Marius M Hoeper: 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: Nick H 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: Gerald Simonneau: Grant monies (from industry related sources) Gerald Simonneau has received grant money paid to his institution from Bayer: Adam Torbicki: University grant monies Adam Torbicki has received university grant monies for statute activities of the university: Martin Wilkins: Consultant fee, speaker bureau, advisory committee, etc. Martin Wilkins has received consulting fees, honorarium and/or support for travel to meetings from Bayer HealthCare: Arno Fritsch: Employee Arno Fritsch is a full-time employee of Bayer HealthCare: Neil Davie: Employee Neil Davie 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 The following authors have nothing to disclose: Chen WangNo Product/Research Disclosure Information.
[Show abstract][Hide abstract] ABSTRACT: Continuous infusion of epoprostenol is the treatment of choice in patients with pulmonary arterial hypertension in functional classes III to IV. However, this treatment's limitations include instability at room temperature. A new epoprostenol formulation offers improved storage conditions and patient convenience.
The EPITOME-2 trial was an open-label, prospective, multicenter, single-arm, phase IIIb study. Patients with pulmonary arterial hypertension on long-term, stable epoprostenol therapy were transitioned from epoprostenol with glycine and mannitol excipients (Flolan; GlaxoSmithKline, Durham, NC) to epoprostenol with arginine and sucrose excipients (Veletri; Actelion Pharmaceuticals Ltd, Allschwil, Switzerland). Patients were followed up for 3 months, and dose adjustments were recorded. Efficacy measures included the 6-minute walk distance, hemodynamics assessed by right heart catheterization, and New York Heart Association functional class. Safety and tolerability of the transition were also evaluated. Quality of life was assessed using the Treatment Satisfaction Questionnaire for Medication.
Forty-two patients enrolled in the study, and 1 patient withdrew consent before treatment; thus, 41 patients received treatment and completed the study. Six patients required dose adjustments. There were no clinically relevant changes from baseline to month 3 in any of the efficacy end points. Adverse events were those previously described with intravenous prostacyclin therapy. Treatment Satisfaction Questionnaire for Medication scores showed an improvement from baseline to month 3 in the domain of treatment convenience.
Transition from epoprostenol with glycine and mannitol excipients to epoprostenol with arginine and sucrose excipients did not affect treatment efficacy, raised no new safety or tolerability concerns, and provided patients with an increased sense of treatment convenience.
Full-text · Article · Feb 2014 · American heart journal
[Show abstract][Hide abstract] ABSTRACT: Background Pulmonary arterial hypertension (PAH) is one of the leading causes of death in systemic sclerosis (SSc). Management of patients with SSc-associated PAH (SSc-PAH) is rapidly evolving and recently reported survival is better than in historical cohorts (albeit still unsatisfactory). However, no data have been reported on purely incident cohorts of patients recruited in the modern management era (2006-2011).
Objectives This study describes the characteristics and outcome of SSc patients prospectively enrolled in the multicentre French PAH registry since 2006
Methods SSc patients (according to American College of Rheumatology and/or Leroy and Medsger’s criteria) enrolled in the registry between January 2006 and November 2009 were prospectively included if they had a precapillary PAH confirmed by right heart catheterization <1 yr prior to enrollment (incident patients with newly diagnosed PAH). Patients with interstitial lung disease (ILD) on high resolution computed tomography (HRCT) were included if forced vital capacity (FVC) >70%.
Results 100 SSc patients were included; 81% were women. Mean age at PAH diagnosis was 65±12 yrs, 86% of patients had limited cutaneous SSc, 80% were in New York Heart Association functional class (NYHA FC) III or IV and 15% had ILD on HRCT, mean FVC and the ratio of diffusing capacity of the lung for carbon monoxide/alveolar volume (DLCO/VA) were 92±20% and 54±20% of predicted values, respectively. At baseline, mean 6-minute walk distance (6MWD) was 266±119m and mean pulmonary vascular resistances were 674±346 dyn.sec.cm-5. Median follow up was 2.4 years with 45 deaths observed; overall survival was 86%, 72%, 52% and 36% at 1, 2, 3 and 4 years, respectively. Univariate analysis identified age (HR: 1.04), NYHA functional class (HR: 4,03), desaturation after 6-minute walk test (HR: 0.90), DLCO/VA (HR: 0.98), presence of an ILD (HR: 2.63) and cardiac index (HR: 0.53) as factors prognostic of survival. Other parameters did not reach statistical significance (p<0.05), including SSc subtype and mPAP.
Conclusions These results confirm the poor prognosis for incident and newly diagnosed SSc-PAH patients even in the modern era of treatment. NYHA functional class, age and presence of an ILD at the diagnosis of PAH were important prognosis factors. Poor right ventricular hemodynamic function and desaturation during the 6-min walk test were also associated with mortality. As 80% of patients are still diagnosed with a NYHA function class III/IV which appears as one of the most important prognosis factor, screening allowing an earlier diagnosis should be a priority.
Disclosure of Interest D. Launay Consultant for: GSK, Actelion, Pfizer, O. Sitbon Consultant for: Actelion, BayerSchering, GSK, Lilly, Novartis, Pfizer and United Therapeutics, J.-F. Cordier Consultant for: GSK, ACTELION, PFIZER, LILLY, E. Hachulla Consultant for: GSK, Actelion, Pfizer, L. Mouthon Consultant for: Octapharma, CSL Behring, LFB Biotechnologies, Cytheris, Actelion, Pfizer, GSK and Lilly, V. Gressin Shareholder of: actelion, Employee of: actelion, L. Rottat: None Declared, P. Clerson: None Declared, G. Simonneau Consultant for: Actelion, BayerSchering, GSK, Novartis, Pfizer and United Therapeutics, M. Humbert Consultant for: Actelion, BayerSchering, GSK, Novartis, Pfizer and United Therapeutics
No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract] ABSTRACT: The current use of intravenous epoprostenol in patients with severe idiopathic, heritable or anorexigen-use associated pulmonary arterial hypertension (IHA-PAH) was investigated.
This observational study evaluated newly diagnosed (≤1year) patients with IHA-PAH, enrolled in the French pulmonary hypertension (PH) registry between 2006 and 2010 and treated with epoprostenol. Among 209 consecutive patients receiving epoprostenol for the treatment of severe PH, 78 had IHA-PAH, including 43 patients naïve of previous PAH-specific treatment.
After 4months of epoprostenol therapy, improvement was observed for treatment naïve patients (n=43) and for patients who had received previous PAH-specific therapy (n=35): NYHA functional class improved in 79% and 44% of these patients, respectively, 6-minute walk distance increased by 146 (p<0.0001) and 41m (p=0.03), cardiac index increased by 1.2 (p<0.0001) and 0.5L·min(-1)·m(-2) (p=0.006), and pulmonary vascular resistance decreased by 700 (p<0.0001) and 299dyn·s·cm(-5) (p=0.009). In the treatment-naïve patient group, upfront combination of epoprostenol and oral PAH therapy tended to be more beneficial compared with epoprostenol monotherapy and was associated with improvement in cardiac index (p=0.03). The observed 1- and 3-year survival estimates from epoprostenol initiation were 84% and 69%, respectively. The highest survival rates were observed for treatment-naïve patients receiving upfront combination of epoprostenol and oral PAH therapy (92% and 88% at 1 and 3years, respectively).
First-line therapy with epoprostenol, especially when combined with oral PAH treatment, was associated with a substantial improvement in clinical and hemodynamic status and favorable survival estimates in patients with severe IHA-PAH.
No preview · Article · Jan 2014 · International journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: In 1998, a clinical classification of pulmonary hypertension (PH) was established, categorizing PH into groups which share similar pathological and hemodynamic characteristics and therapeutic approaches. During the 5th World Symposium held in Nice, France, in 2013, the consensus was reached to maintain the general scheme of previous clinical classifications. However, modifications and updates especially for Group 1 patients (pulmonary arterial hypertension [PAH]) were proposed. The main change was to withdraw persistent pulmonary hypertension of the newborn (PPHN) from Group 1 because this entity carries more differences than similarities with other PAH subgroups. In the current classification, PPHN is now designated number 1. Pulmonary hypertension associated with chronic hemolytic anemia has been moved from Group 1 PAH to Group 5, unclear/multifactorial mechanism. In addition, it was decided to add specific items related to pediatric pulmonary hypertension in order to create a comprehensive, common classification for both adults and children. Therefore, congenital or acquired left-heart inflow/outflow obstructive lesions and congenital cardiomyopathies have been added to Group 2, and segmental pulmonary hypertension has been added to Group 5. Last, there were no changes for Groups 2, 3, and 4.
Full-text · Article · Dec 2013 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Pulmonary hypertension (PH), a common complication of left heart diseases (LHD), negatively impacts symptoms, exercise capacity, and outcome. Although the true prevalence of PH-LHD is unknown, a subset of patients might present significant PH that cannot be explained by a passive increase in left-sided filling pressures. The term "out-of-proportion" PH has been used to identify that population without a clear definition, which has been found less than ideal and created confusion. We propose a change in terminology and a new definition of PH due to LHD. We suggest to abandon "out-of-proportion" PH and to distinguish "isolated post-capillary PH" from "post-capillary PH with a pre-capillary component" on the basis of the pressure difference between diastolic pulmonary artery pressure and pulmonary artery wedge pressure. Although there is no validated treatment for PH-LHD, we provide insights into management and discuss completed and randomized trials in this condition. Finally, we provide recommendations for future clinical trials to establish safety and efficacy of novel compounds to target this area of unmet medical need.
Full-text · Article · Dec 2013 · Journal of the American College of Cardiology
[Show abstract][Hide abstract] ABSTRACT: Chronic obstructive lung disease (COPD) and diffuse parenchymal lung diseases (DPLD), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis, are associated with a high incidence of pulmonary hypertension (PH), which is linked with exercise limitation and a worse prognosis. Patients with combined pulmonary fibrosis and emphysema (CPFE) are particularly prone to the development of PH. Echocardiography and right heart catheterization are the principal modalities for the diagnosis of COPD and DPLD. For discrimination between group 1 PH patients with concomitant respiratory abnormalities and group 3 PH patients (PH caused by lung disease), patients should be transferred to a center with expertise in both PH and lung diseases for comprehensive evaluation. The task force encompassing the authors of this article provided criteria for this discrimination and suggested using the following definitions for group 3 patients, as exemplified for COPD, IPF, and CPFE: COPD/IPF/CPFE without PH (mean pulmonary artery pressure [mPAP] <25 mm Hg); COPD/IPF/CPFE with PH (mPAP ≥25 mm Hg); PH-COPD, PH-IPF, and PH-CPFE); COPD/IPF/CPFE with severe PH (mPAP ≥35 mm Hg or mPAP ≥25 mm Hg with low cardiac index [CI <2.0 l/min/m(2)]; severe PH-COPD, severe PH-IPF, and severe PH-CPFE). The "severe PH group" includes only a minority of chronic lung disease patients who are suspected of having strong general vascular abnormalities (remodeling) accompanying the parenchymal disease and with evidence of an exhausted circulatory reserve rather than an exhausted ventilatory reserve underlying the limitation of exercise capacity. Exertional dyspnea disproportionate to pulmonary function tests, low carbon monoxide diffusion capacity, and rapid decline of arterial oxygenation upon exercise are typical clinical features of this subgroup with poor prognosis. Studies evaluating the effect of pulmonary arterial hypertension drugs currently not approved for group 3 PH patients should focus on this severe PH group, and for the time being, these patients should be transferred to expert centers for individualized patient care.
Full-text · Article · Dec 2013 · Journal of the American College of Cardiology