Search

Pulmonary hypertension (PH) comprises a heterogeneous group of disorders characterised by increased pulmonary vascular resistance that results in progressive right ventricular failure. In order to translate current evidence into routine clinical practice, the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) have recently jointly proposed evidence-based guidelines for the optimal management of different PH patient groups. This article describes a series of clinical cases of PH due to various aetiologies that were referred to a large national PH expert referral centre. In each case, the assessment and therapeutic approach undertaken is described in the context of the new ECS/ERS guidelines. The routine diagnostic work-up of suspected idiopathic pulmonary arterial hypertension (PAH) and recommended treatments for patients with functional class II, III and IV disease is emphasised. Familial screening and management of heritable PAH is discussed. Appropriate investigation and therapeutic strategies for patients with chronic thromboembolic disease and PH that is associated with congenital heart disease, pulmonary veno-occlusive disease and systemic sclerosis are also highlighted.

A goal-oriented treatment strategy is recommended in patients with pulmonary arterial hypertension (PAH). The current treatment goals are based on regular assessment of clinical parameters that have been demonstrated as prognostic factors at the time of initial evaluation. The prognostic value of the course of these parameters assessed at follow-up on PAH-specific therapies is unknown. The aim of the EFORT clinical study is to analyse the prognostic factors assessed at follow-up in patients with PAH, to provide more accurate information in terms of treatment goals than the simple analysis of prognostic factors at baseline. This clinical research project should help to establish new recommendations for the management of patients with PAH. The impact of these new therapeutic approaches on long-term survival of patients with PAH is a major challenge in the near future.

Aims To assess the acute vasodilator response and long-term response to calcium-channel blockers (CCB) in pulmonary arterial hypertension (PAH) with associated conditions. Methods and results The response to acute vasodilator testing [>20% decrease in mean pulmonary artery pressure (mPAP) and total pulmonary resistance] was assessed in 663 consecutive PAH patients with connective tissue disease (CTD; n = 168), portal hypertension (PoPH; n = 153), anorexigen use ( n = 127), human immunodeficiency virus infection (HIV; n = 124), congenital heart disease (CHD; n = 50), and pulmonary veno-occlusive disease or capillary haemangiomatosis (PVOD/PCH; n = 41). An acute vasodilator response was observed in 13.4% of PAH-anorexigen patients, 12.2% of PVOD/PCH, 10.1% of CTD, 1.6% of HIV, 1.3% of PoPH, and was absent in CHD. A long-term response to CCB (marked haemodynamic improvement at 3–4 months and New York Heart Association functional class I or II after 1 year) was reported in 9.4% of PAH-anorexigen patients but was rare in HIV, PoPH, CTD (1.6, 0.7, and 0.6%, respectively) and absent in PVOD/PCH. All patients with a long-term CCB response were alive after 5 years; two deaths not related to PAH occurred after this time. Recent criteria for acute response based on the fall in mPAP to

SummaryPulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary arterial hypertension characterised by a progressive obstruction of small pulmonary veins that leads to elevation in pulmonary vascular resistance and right ventricular failure. Despite improved understanding and more efficacious treatment options for PAH overall, the prognosis of PVOD remains dismal. Without therapeutic intervention few patients would be expected to survive more than two years. PVOD may occur in both idiopathic and heritable forms, or develop in association with connective tissue disease, chronic respiratory disease, malignancy or bone marrow transplantation, among other causes. A widespread fibrous intimal proliferation that predominantly involves the pulmonary venules and small veins is the key histopathological hallmark. Surgical lung biopsy is considered the definitive diagnostic test but is associated with significant risk and is not recommended. Distinguishing PVOD from PAH on clinical grounds alone is generally not possible, although PVOD is characterised by a higher male/female ratio and higher tobacco exposure. Instead, non-invasive tests may be helpful and the diagnosis is usually based on an integrated assessment that incorporates high resolution computed tomography (septal lines, ground-glass opacities and lymph node enlargement), pulmonary function testing (lower DLCO), arterial blood gas analysis (lower PaO2 at rest) and bronchoalveolar lavage (occult alveolar haemorrhage). Treatment of PVOD remains challenging as exposure to pulmonary vasodilators and PAH-specific agents may precipitate acute pulmonary oedema. Nonetheless, a number of successful outcomes describing cautious use of prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors have been described. Unfortunately, the long term effects of these agents are variable and lung transplantation remains the treatment of choice.

At diagnosis of pulmonary arterial hypertension (PAH), some patients are considered to have a "near-normal" 6-min walk distance (6MWD) (ie,450 m). Because they are generally excluded from randomized controlled trials, little is known about these patients.We analyzed the baseline characteristics and treatment responses of 49 consecutive patients with a 6MWD450 m at the time of newly diagnosed PAH. Data from this cohort were then compared with data from hemodynamically matched patients with a 6MWDor = 450 m.Patients with a 6MWD450 m were either in World Health Organization (WHO) functional class (FC) II (n = 23) or III (n = 26) at baseline. Compared with patients in FC II, those in FC III had more severe hemodynamic impairment (ie, a lower cardiac index and higher pulmonary vascular pressures and resistance) but similar 6MWD. At first evaluation after initiation of PAH-specific treatment (3-6 months), FC improved (FC I-II: n = 38; FC III: n = 11, P.005) and cardiac index increased. However, 6MWD remained unchanged. Compared with matched patients with a 6MWDor = 450 m (n = 98), individuals with a 6MWD450 m were approximately 9 years younger (P = .0006) and had a lower BMI (P = .0009).Anthropometric characteristics such as younger age and lower BMI may explain higher 6MWD in some PAH patients. In the cohort of patients with a 6MWD450 m, hemodynamic indices and WHO FC were more sensitive than 6MWD in detecting changes secondary to PAH-specific treatments.

International audience; BACKGROUND: Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH) in COPD patients. We hypothesized that the risk for PH in COPD is increased by an elevation in the proinflammatory cytokines interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1beta, as well as by specific genetic polymorphisms of these cytokines. METHODS: We assessed cytokine plasma levels and the polymorphisms G(-174)C IL-6, C(-511)T IL-1beta, and A(-2518)G MCP-1 in 148 COPD patients (recruited at two centers) with right heart catheterization data and 180 control subjects including smokers and nonsmokers. Human pulmonary artery smooth muscle cells (PA-SMCs) were cultured for IL-6 messenger RNA assays under normoxic and hypoxic conditions. RESULTS: Patients with PH (mean pulmonary artery pressure [PAP], >or= 25 mm Hg) had lower Pao(2) and higher plasma IL-6 values than those without PH; there were no differences in terms of pulmonary function test results or CT scan emphysema scores. Plasma IL-6 correlated with mean PAP (r = 0.39; p < 0.001) and was included in a multiple stepwise regression analysis, with mean PAP as the dependent variable. In patients with the IL-6 GG genotype, the mean PAP value was significantly higher and PH was more common than in CG or CC patients (adjusted odds ratio, 4.32; 95% confidence interval, 1.96 to 9.54). Exposure to 4 h of hypoxia led to an about twofold increase in IL-6 messenger RNA in cultured human PA-SMCs. CONCLUSIONS: Inflammation, most likely involving IL-6, may contribute substantially to PH complicating COPD.

Bosentan has proven 4-month efficacy in patients with HIV-associated pulmonary arterial hypertension (PAH-HIV). Herein, the long-term outcome of unselected PAH-HIV patients treated with first-line bosentan is described. Data for 59 consecutive World Health Organization (WHO) functional class II-IV PAH-HIV patients treated with first-line bosentan between May 2002 and July 2007 were analysed. HIV status, 6-min walk distance and haemodynamics were assessed at baseline, after 4 months and every 6-12 months thereafter. After 4 months, 6-min walk distance increased from 358+/-98 to 435+/-89 m and pulmonary vascular resistance decreased from 737+/-328 to 476+/-302 dyn x s x cm(-5). At the final evaluation (29+/-15 months), 6-min walk distance remained stable and pulmonary vascular resistance decreased further to 444+/-356 dyn x s x cm(-5). Haemodynamics normalised in 10 patients. At their last evaluation, these 10 patients were in WHO functional class I, with a 6-min walk distance of 532+/-52 m. Overall survival estimates were 93, 86 and 66% at 1, 2 and 3 yrs, respectively. Bosentan was safe when combined with highly active antiretroviral therapy, with no negative impact on HIV infection control. The present data confirm the long-term benefits of bosentan therapy in HIV-associated pulmonary arterial hypertension patients with improvements in symptoms, 6-min walk distance and haemodynamics, and with favourable overall survival.

Serotonin [5-hydroxytryptamine (5-HT)] biosynthesis depends on two rate-limiting tryptophan hydroxylases (Tph): Tph1, which is expressed in peripheral organs, and Tph2, which is expressed in neurons. Because 5-HT is involved in pulmonary hypertension (PH), we investigated whether genetic variations in Tph1 and/or Tph2 affected PH development in mice. To examine the functional impact of peripheral Tph1 deficiency on hypoxic PH, we used Tph1−/− mice characterized by very low 5-HT synthesis rates and contents in the gut and lung and increased 5-HT synthesis in the forebrain. With chronic hypoxia, 5-HT synthesis in the forebrain increased further. Hypoxic PH, right ventricular hypertrophy, and distal pulmonary artery muscularization were less severe ( P < 0.001) than in wild-type controls. The Tph inhibitor p-chlorophenylalanine (100 mg·kg−1·day−1) further improved these parameters. We then investigated whether mouse strains harboring the C1473G polymorphism of the Tph2 gene showed different PH phenotypes during hypoxia. Forebrain Tph activity was greater and hypoxic PH was more severe in C57Bl/6 and 129X1/SvJ mice homozygous for the 1473C allele than in DBA/2 and BALB/cJ mice homozygous for the 1473G allele. p-Chlorophenylalanine reduced PH in all groups and abolished the difference in PH severity across mouse strains. Hypoxia increased 5-hydroxytryptophan accumulation but decreased 5-HT contents in the forebrain and lung, suggesting accelerated 5-HT turnover during hypoxia. These results provide evidence that dysregulation of 5-HT synthesis is closely linked to the hypoxic PH phenotype in mice and that Tph1 and Tph2 may contribute to PH development.

Results: In-hospital mortality was 15% (4/26) and in-hospital morbidity was 27% (7/26). Causes of death included cerebral hemorrhage (n= 1), pneumonia (n= 2) and right heart failure (n= 1). By univariate analysis, only residual pulmonary hypertension (mPAP > 30mmHg) (p= 0.03) was associated with early mortality. Survival at 1-year was 80% by Kaplan-Meier analysis. Conclusion: PEA for CTEPH in octogenarians provides acceptable postoperative mortality and excellent long-term survival in highly select patients. Advanced age should not be a contraindication for PEA in cases where good hemodynamic results are expected.

Les patients souffrant d’hypertension arterielle pulmonaire (HTAP) et repondant aux conditions d’urgence vitale peuvent acceder a une transplantation pulmonaire (TP) ou cardio-pulmonaire (TCP) en Super Urgence (SU) depuis 09/2006 et 07/2007 respectivement. Objectifs et methodes Etudier les resultats de la TP et de la TCP en SU dans l’HTAP. Les caracteristiques et le devenir de ces patients ont ete retrospectivement analyses et compares aux patients greffes sur liste conventionnelle a l’ere de la SU (2007–2013) et avant l’ere de la SU (2000–2006). Resultats De 2007 a 2013, 26/50 (52 %) TP et 31/45 (69 %) TCP ont ete realisees en SU. En preoperatoire, 47/57 (82 %) des patients greffes en SU etaient sous amines et 17/57 (30 %) etaient sous assistance circulatoire. La survie postoperatoire a 1,2,3 et 5 ans des greffes en SU n’etait pas significativement differente de celle des greffes sur liste conventionnelle (67 %, 61 %, 56 % et 53 % vs 84 %, 75 %, 68 % et 68 % respectivement, p = 0,1). Les deux groupes etaient similaires en termes de duree de ventilation mecanique et incidence de dysfonction primaire du greffon. A l’ere de la SU, le ratio nombre de deces sur liste/nombre de greffes a significativement diminue en comparaison a la periode 2000–2006 (0,15 ± 0,11 vs 0,96 ± 0,46, p Conclusion Cette etude suggere que la SU pourrait ameliorer la survie des patients souffrant d’HTAP et inscrits sur liste de transplantation sans aggravation significative de la morbidite et mortalite post-operatoire.

Introduction La maladie veino-occlusive pulmonaire (MVOP) est une forme rare d’hypertension pulmonaire caracterisee par un remodelage vasculaire pulmonaire predominant sur les veinules et les capillaires pulmonaires. La MVOP peut survenir dans un contexte idiopathique ou heritable. Des cas cliniques isoles ont aussi rapporte la survenue de MVOP chez des patients recevant de la chimiotherapie, sans qu’aucune molecule ne puisse specifiquement etre identifiee comme facteur de risque. Resultats Entre 2012 et 2014, 6 cas de MVOP ont ete identifies dans le reseau francais de l’HTAP chez des patients traites par mitomycine pour un cancer epidermoide du canal anal. L’âge median etait de 51 ans avec une predominance feminine (5F/1H). La MVOP survenait 4 mois (min–max 2–6) apres la fin de la chimiotherapie. Au diagnostic, les patients avaient un retentissement clinique, fonctionnelle et hemodynamique severe et leur pronostic etait severe (4 deces dans le suivi). Afin d’etudier la relation entre mitomycine et MVOP, nous avons etudie l’effet de l’administration de mitomycine chez l’animal. L’injection intraperitoneale de mitomycine chez le rat a entraine la survenue d’hypertension pulmonaire, et d’un intense remodelage des veines et capillaires pulmonaires, mimant la MVOP humaine. Conclusion L’identification de cas de MVOP induite par la mitomycine a permis de confirmer le role potentiel des agents alkylants dans la survenue de MVOP chez l’homme. La mise au point du premier modele animal de MVOP represente une opportunite unique de mieux comprendre la physiopathologie de la MVOP et d’evaluer des therapies innovantes dans cette maladie sans traitement a ce jour.

Les strategies therapeutiques actuelles, exposees dans les recommandations ERS/ESC 2009, ont permis une amelioration de l'esperance et de la qualite de vie des malades atteints d'hypertension arterielle pulmonaire, mais demeurent insuffisantes pour envisager un traitement curatif de la maladie. Afin d'ameliorer le pronostic de l'hypertension arterielle pulmonaire, plusieurs pistes sont envisagees ou sont en cours d'evaluation: developper de nouvelles molecules, developper de nouvelles strategies de combinaison de traitement ou evaluer de nouvelles cibles therapeutiques. Un des objectifs est d'optimiser en termes d'efficacite et de tolerance les traitements ciblant les voies de signalisation classiques du NO, de l'endotheline ou de la prostacycline. De nouvelles strategies therapeutiques ciblant plus directement la proliferation anormale des cellules vasculaires pulmonaires telles que les inhibiteurs de tyrosine kinases sont en cours d'evaluation. Enfin, les essais cliniques evaluant les combinaisons de traitements montrent des resultats encourageants.

A goal-oriented treatment strategy is recommended in patients with pulmonary arterial hypertension (PAH). The current treatment goals are based on regular assessment of clinical parameters that have been demonstrated as prognostic factors at the time of initial evaluation. The prognostic value of the course of these parameters assessed at follow-up on PAH-specific therapies is unknown. The aim of the EFORT clinical study is to analyse the prognostic factors assessed at follow-up in patients with PAH, to provide more accurate information in terms of treatment goals than the simple analysis of prognostic factors at baseline. This clinical research project should help to establish new recommendations for the management of patients with PAH. The impact of these new therapeutic approaches on long-term survival of patients with PAH is a major challenge in the near future.

Abstract 572 Introduction : Pulmonary hypertension (PH) has emerged as life threatening complication in patients with sickle cell disease. It is usually diagnosed at echocardiography by estimating systolic Pulmonary Artery Pressure (PAP) through the measurement of a velocity of tricuspid regurgitation (TRV) > 2.5 m/s. Pulmonary Hypertension diagnosed as so could affect up to 30% of patients with sickle cell disease (SCD). However, according to most guidelines, PH is rather defined by measurement of mean PAP ≥ 25 mmHg at right heart catheterism. Whether measurement of TRV ≥ 2.5 m/s at echocardiography accurately identifies patients with PH in patients with SCD, has never been evaluated. We conducted a prospective multicentre study in 403 consecutive adult out-patients in stable clinical condition, recruited after informed consent, during 2 years (from Feb.2007 to March 2009) from 2 SCD referral centers in France (1 in Paris and 1 in Martinique). Follow -up was planned for 3 years. All patients had Doppler echocardiography, pulmonary function tests and 6 min walk test. RHC was systematically performed in case of TRV3 2.5m/sec. Results. Of the 385/403 patients (SS in 379, 6 Sb0thalassemia) with all data availabel, sex ratio 1.5 , mean age 34±10 yrs, 96 had TRV 3 2.5m/s (25 %) and underwent RHC. There was no PH in 72/96 with mPAp=19 ±3mmHg (false positive of echocardiography=75%). In 24 patients, m PAP was elevated (30 ± 0.4m/s). Mechanism of PH was: post-capillary PH in 13 patients (elevated pulmonary capillary wedge pressure) - hyperkinetic state in 5 patients (high cardiac output, normal pulmonary vascular resistance) - pre-capillary pulmonary arterial hypertension (PAH) in 6 patients (normal capillary wedge pressure, increased vascular resistance). Patients with a confirmed PH at RHC were significantly older (45 vs 33 yrs), had higher LDH, NT-Pro BNP, and a lower 6 min walk distance. There was no influence of long term treatment (hydroxyurea, chronic transfusion) on PH. During follow-up (mean=11 months), 3 patients died, all in the group of patients with TRV32.5 m/sec and confirmed PH at RHC (mPAP 3 25 mmHg). The 24 patients having confirmed PH with RHC display similar biological and hemodynamic profile to the 18/42 with TRV3 2.5m/sec among the 195 patients (132 SS,35SC,23S-Thalassemia b0or b+) of the Gladwin study(1), consenting to have RHC. The use of a higher cut-off value of TRV, 2.8 m/sec, decreases the false positive rate from 75% to 50%. However, 29% of patients with pulmonary hypertension (7/24) would have been undiagnosed. Conclusion PH confirmed by gold-standard technique (RHC) is relatively rare among SCD patients, with a prevalence of 24/385 (6%). PAH was present in only 6 patients (1.6%). In this population, a TRV 2.5m/s on Doppler echocardiography is inadequate to diagnose PH. The loose relationship found between TRV and pulmonary hypertension in patients with sickle cell disease does not support its use as a routine screening tool, whatever the cut-off used. Although PH on RHC was generally modest, PH seems to be an important prognostic factor. The large difference on mortality compared to previous studies will be discussed. Disclosures: No relevant conflicts of interest to declare.

Introduction et objectifs L’impact des traitements actuels de l’infection VIH (HAART) et des traitements specifiques de l’hypertension arterielle pulmonaire (HTAP) sur la severite et le pronostic de l’HTAP associee a l’infection VIH (HTAP-VIH) est mal connu. Les objectifs de cette etude etaient de determiner les facteurs pronostiques au cours l’HTAP-VIH a l’heure des traitements modernes. Materiels et methodes Analyse retrospective des donnees de tous les patients consecutifs ayant une HTAP-VIH sans autre facteur de risque pour l’HTAP vus dans le Centre National de Reference de l’HTAP entre 10/2000 et 1/2008. Resultats 77 patients (58 % hommes, âge moyen 41 ans, anciennete de l’infection VIH 11,1 ans, toxicomanie 36 %). Lors du diagnostic d’HTAP, 81 % des patients recevaient HAART, 79 % avaient des CD4+ >200/mm 3 et 49 % une charge virale indetectable. La classe NYHA etait : II (22 %), III (69 %) et IV (9 %). La distance de marche mediane au test de marche de 6 minutes (DM6’) etait de 375 m, et les resistances vasculaires pulmonaires medianes de 689 d.s.cm −5 . Tous les patients ont ete traites par HAART (quel que soit leur statut VIH) et 50 ont recu un traitement specifique de l’HTAP, conduisant a une amelioration de la DM6’ et de l’hemodynamique. Chez les patients ayant recu HAART sans traitement specifique de l’HTAP, la DM6’ s’est amelioree mais l’hemodynamique ne s’est pas modifiee. La survie globale etait 88 % a 1 an et de 72 % a 3 ans. En analyse multivariee, un index cardiaque > 2,8 L/min/m 2 et untaux de CD4+ > 200/mm 3 etaient des facteurs pronostiques independants de survie. Conclusion Chez les patients HTAP-VIH, un traitement antiretroviral seul (HAART) ne permet pas d’amelioration hemodynamique. Le pronostic des patients HTAP-VIH est essentiellement lie aux taux de CD4+ et a la fonction cardiaque.

Congenital portosystemic shunts are increasingly recognized in several settings and at any age. The following are some of the most common presentations: prenatal ultrasound, neonatal cholestasis, incidental finding on abdominal imaging, or systemic complications such as unexplained cardiopulmonary or neurological disease, or the presence of liver nodules in a noncirrhotic liver. The purpose of the present review is to summarize clinical presentation and current recommendations for management, and highlight areas of future research. Illustrative examples from the veterinary literature complement our current lack of knowledge of this rare malformation often masquerading as a multisystem disease.

Rationale: Pulmonary veno-occlusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) characterized by progressive obstruction of small pulmonary veins. Limited case series have reported a possible association between different chemotherapeutic agents and PVOD. Methods: We evaluated the relationship between chemotherapeutic agents and PVOD. Cases of chemotherapy-induced PVOD from the French PH network and literature were reviewed. Consequences of chemotherapy exposure on the pulmonary vasculature and hemodynamics were investigated in three different animal species (mouse, rat and rabbit). Results: Thirty-seven cases of chemotherapy-associated PVOD were identified in the French PH network and systematic literature analysis. Exposure to alkylating agents was observed in 83.8% of cases, mostly represented by cyclophosphamide (CP, 43.2%). In experimental models, CP exposure induced PH in the 3 different animal species. In rats, the severity of PH and vascular remodeling was sex-dependent (females more susceptible than males), time-dependent, and dose-dependent. We also demonstrate in rats that amifostine pre-treatment improved survival and ameliorated PH severity after CP exposure. Rabbits exposed to CP displayed features of congestive lungs and venular involvement, mimicking human PVOD. Interestingly, CP-exposure was associated with recognized triggers of PAH: raise in pulmonary serotonin content, overproduction of endothelin-1, or vascular inflammation among others. Conclusions: Clinical data and animal models demonstrated a plausible cause-effect relationship between alkylating agents and PVOD. Clinicians should be aware of this uncommon but severe pulmonary vascular complication of alkylating agents.

Background Inflammation may contribute to the pathogenesis of various forms of pulmonary hypertension (PH). Recent studies in patients with idiopathic PH or PH associated with underlying diseases suggest a role for interleukin-6 (IL-6). Methods To determine whether endogenous IL-6 contributes to mediate hypoxic PH and lung inflammation, we studied IL-6-deficient (IL-6-/-) and wild-type (IL-6+/+) mice exposed to hypoxia for 2 weeks. Results Right ventricular systolic pressure, right ventricle hypertrophy, and the number and media thickness of muscular pulmonary vessels were decreased in IL-6-/- mice compared to wild-type controls after 2 weeks' hypoxia, although the pressure response to acute hypoxia was similar in IL-6+/+ and IL-6-/- mice. Hypoxia exposure of IL-6+/+ mice led to marked increases in IL-6 mRNA and protein levels within the first week, with positive IL-6 immunostaining in the pulmonary vessel walls. Lung IL-6 receptor and gp 130 (the IL-6 signal transducer) mRNA levels increased after 1 and 2 weeks' hypoxia. In vitro studies of cultured human pulmonary-artery smooth-muscle-cells (PA-SMCs) and microvascular endothelial cells revealed prominent synthesis of IL-6 by PA-SMCs, with further stimulation by hypoxia. IL-6 also markedly stimulated PA-SMC migration without affecting proliferation. Hypoxic IL-6-/- mice showed less inflammatory cell recruitment in the lungs, compared to hypoxic wild-type mice, as assessed by lung protein levels and immunostaining for the specific macrophage marker F4/80, with no difference in lung expression of adhesion molecules or cytokines. Conclusion These data suggest that IL-6 may be actively involved in hypoxia-induced lung inflammation and pulmonary vascular remodeling in mice.

International audience; Background: Venous thromboembolism is a major complication of coronavirus disease 2019 (COVID-19). We hypothesized that a weight-adjusted intermediate dose of anticoagulation may decrease the risk of venous thromboembolism COVID-19 patients.Methods: In this multicenter, randomised, open-label, phase 4, superiority trial with blinded adjudication of outcomes, we randomly assigned adult patients hospitalised in 20 French centers and presenting with acute respiratory SARS-CoV-2. Eligible patients were randomly assigned (1:1 ratio) to receive an intermediate weight-adjusted prophylactic dose or a fixed-dose of subcutaneous low-molecular-weight heparin during the hospital stay. The primary outcome corresponded to symptomatic deep-vein thrombosis (fatal) pulmonary embolism during hospitalization (COVI-DOSE ClinicalTrials.gov number: NCT04373707).Findings: Between May 2020, and April 2021, 1000 patients underwent randomisation in medical wards (noncritically ill) (80.1%) and intensive care units (critically ill) (19.9%); 502 patients were assigned to receive a weight-adjusted intermediate dose, and 498 received fixed-dose thromboprophylaxis. Symptomatic venous thromboembolism occurred in 6 of 502 patients (1.2%) in the weight-adjusted dose group and in 10 of 498 patients (2.1%) in the fixed-dose group (subdistribution hazard ratio, 0.59; 95% CI, 0.22-1.63; P = 0.31). There was a twofold increased risk of major or clinically relevant nonmajor bleeding: 5.9% in the weight-adjusted dose group and 3.1% in the fixed-dose group (P = 0.034).Interpretation: In the COVI-DOSE trial, the observed rate of thromboembolic events was lower than expected in patients hospitalized for COVID-19 infection, and the study was unable to show a significant difference in the risk of venous thromboembolism between the two low-molecular-weight-heparin regimens.

Background. Respiratory comorbidities are common in cirrhotic patients and may influence the decision for liver transplantation (LT). Our objective was to determine their prevalence and prognostic value. Method. NYHA functional class (FC), 6-minute walk distance (6MWD), arterial blood gases, lung function tests, right heart catheterization and heptopulmonary syndrome (HPS) screening were performed in 289 patients listing for LT. The prognostic value of respiratory parameters was analyzed over a period of 10 years. Results. The mean age was 52 ± 8 years (78% males, 72% Child-Pugh (CP) stage B or C). 36% were in NYHA-FC II or more, 47% had hypoxemia and 15% had obstructive ventilatory disorder. The prevalence of hepatic hydrothorax (HH), HPS and portopulmonary hypertension (PoPH) was respectively 6.6%, 12.4% and 1.4%. 6MWD was positively correlated with hemoglobin (p