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Copyright of EMC-Pneumologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of EMC-Pneumologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The REPLACE study showed that switching to riociguat (rio) can benefit pulmonary arterial hypertension (PAH) patients treated with phosphodiesterase type 5 inhibitors (PDE5i) but still at intermediate risk. Improvements to lower risk status with rio versus PDE5i were seen with all three risk assessment tools analyzed, although the difference was not statistically significant with the modified REVEAL risk score (mRRS). Here, we report changes in the components of the mRRS, COMPERA, and FPHN non-invasive risk assessment tools, and a post hoc analysis of RRS Lite 2 in REPLACE. Individual components of mRRS, COMPERA, and FPHN non-invasive assessment tools, and RRS Lite 2 risk scores and risk strata were calculated for the rio group (n=111) and PDE5i group (n=113) at REPLACE baseline and Week 24. WHO/NYHA functional class (FC), 6MWD, and NT-proBNP were components of all risk scores. Vital signs (systolic blood pressure [SBP] and heart rate [HR]) and renal insufficiency were additional components for mRRS and RRS Lite 2. PAH etiology and demographics were also components of mRRS. For mRRS, COMPERA, and FPHN, 44% of patients in the rio group vs 23% in the PDE5i group improved their WHO/NYHA FC component score at Week 24. Similar results were found for the 6MWD component (1 point removed from mRRS: rio 41% vs PDE5i 27%; COMPERA grade 1/FPHN low risk at Week 24: rio 37% vs PDE5i 27%). The incidences of lowest-risk NT-proBNP component scores at Week 24 were rio 41% vs PDE5i 40% for mRRS, rio 21% vs PDE5i 12% for COMPERA, and rio 41% vs PDE5i 40% for FPHN. At baseline, mRRS vital sign scores were similar between the two groups. At Week 24, more patients in the rio group (50%) versus the PDE5i group (36%) had 1−2 points added to their mRRS score due to SBP <110 mmHg and/or HR >96 bpm. The overall result was similar for the mRRS and the RRS Lite 2. With RRS Lite 2, the proportion of patients achieving a low-risk stratum from baseline to Week 24 was 41% to 61% for rio and 37% to 50% for PDE5i. Risk assessment tools showed similar trends in shared components between treatment groups at baseline and Week 24. Results with RRS Lite 2 were similar to mRRS. Differences in discrimination of the risk sores, weighting of components, and differences in the vital signs component of mRRS could explain between score differences at baseline and Week 24 in REPLACE. SBP and HR will be individually analyzed in future. [ABSTRACT FROM AUTHOR]

The aim of a clinical classification of pulmonary hypertension (PH) is to group together different manifestations of disease sharing similarities in pathophysiologic mechanisms, clinical presentation, and therapeutic approaches. In 2003, during the 3rd World Symposium on Pulmonary Hypertension, the clinical classification of PH initially adopted in 1998 during the 2nd World Symposium was slightly modified. During the 4th World Symposium held in 2008, it was decided to maintain the general architecture and philosophy of the previous clinical classifications. The modifications adopted during this meeting principally concern Group 1, pulmonary arterial hypertension (PAH). This subgroup includes patients with PAH with a family history or patients with idiopathic PAH with germline mutations (e.g., bone morphogenetic protein receptor-2, activin receptor-like kinase type 1, and endoglin). In the new classification, schistosomiasis and chronic hemolytic anemia appear as separate entities in the subgroup of PAH associated with identified diseases. Finally, it was decided to place pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis in a separate group, distinct from but very close to Group 1 (now called Group 1'). Thus, Group 1 of PAH is now more homogeneous. [ABSTRACT FROM AUTHOR]

Purpose. – Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction, in situ thrombosis and vascular remodeling of small pulmonary arteries inducing a fixed pulmonary arterial obstruction and persistent elevation of pulmonary arterial resistance. Conventional treatment is based on simple measures (exercise limitation) and non-specific drugs (warfarine, diuretics, oxygen).Current knowledge and key points. – Pure vasodilators like calcium channel antagonists have little or no effect on the vast majority of patients, presumably because fixed pulmonary arteriopathy predominate over vasoconstriction. Intravenous prostacyclin (epoprostenol) and endothelin receptor antagonists have vasodilator and antiproliferative properties. Epoprostenol therapy has resulted in significant improvements in prognosis of this disease and this drug remains the first-line treatment of the most severe patients. Bosentan is an interesting first-line treatment for NYHA functional class III patients. Availability of novel specific drugs (endothelin receptor type A antagonists, prostacyclin analogues, type 5 phosphodiesterase inhibitors) open new perspectives in treatment of PAH. The long-term benefit of these drugs remains to be evaluated and their respective place in treatment of these patients is still uncertain. We here present the different therapeutic alternatives available in the PAH and propose an algorithm for treatment of these patients.Future prospects and projects. – The evolution of therapy from vasodilators to antiproliferative agents reflects the advancement in our understanding of the mechanisms mediating pulmonary arterial hypertension. [Copyright &y& Elsevier]

Purpose. – Pulmonary hypertension is a rare but well-known life-threatening complication of connective tissue diseases. The aim of this article is to analyse the available literature and to report the experience of a pulmonary vascular diseases centre about this complication.Current knowledge and key points. – Scleroderma and its limited variant, the CREST syndrome (calcification, Raynaud phenomenon, esophageal dysmotility, sclerodactily, telangiectasia), is the most common connective tissue disease affected by pulmonary hypertension. Dyspnea is the main symptom and is frequently severe. Echocardiography is an excellent exam to detect pulmonary hypertension. However, right heart catheterization is necessary to confirm the diagnosis of pulmonary hypertension and to test vasoreactivity with a potent vasodilator such as nitric oxide. Pulmonary hypertension is less severe in patients with connective tissue diseases perhaps because of an earlier diagnosis. A significantly lower proportion of patients presents an acute vasodilator response, suggesting an early constitution of irreversible pulmonary vascular lesions. Continuous intravenous epoprostenol therapy seems to be less effective as compared with patients with primitive pulmonary hypertension and does not improve survival. So, we observed dramatic improvement in rare cases after immunosuppressive therapy.Future prospects and projects. – New treatments with oral, subcutaneous or inhaled stable prostacyclin analogs or with an endothelin receptor antagonist are currently being evaluated. The role of immunosuppressive therapy has to be defined. [ABSTRACT FROM AUTHOR]

In TRITON (NCT02558231), initial triple (macitentan, tadalafil, selexipag) and initial double (macitentan, tadalafil, placebo) oral therapy in newly diagnosed PAH patients markedly improved hemodynamic and functional parameters at week 26, with no difference between groups. Main analysis up to end of main observation period suggested that initial triple therapy reduced the risk of disease progression vs initial double therapy. Here, we present data from a longer follow-up period (up to end of study [EOS]). In this multicenter, double-blind, randomized, placebo-controlled, phase 3b study, end of the main observation period occurred when the last patient randomized completed week 26. Unblinding occurred after end of main observation period, and patients were further followed-up to EOS, which occurred 30 days after last intake of study treatment. Time to first disease progression event (pre-specified) and all-cause death (post-hoc) were analyzed with Cox regression; all disease progression events were analysed (post-hoc) using a negative binomial model. Events were centrally adjudicated in a blinded fashion. Median follow-up time at EOS was 100 weeks in the initial triple therapy group (n=123) and 95 weeks in the initial double therapy group (n=124) (Table). The hazard ratio for the risk of a first disease progression event and the rate of all disease progression events for initial triple vs initial double therapy were similar at end of main observation period and at EOS (Table). Four patients in the initial triple and 12 in the initial double therapy groups died before EOS. Safety up to EOS was consistent with findings at end of main observation period. Results at EOS and at end of main observation period are consistent and suggest a signal for improved long-term outcome with initial triple vs initial double oral therapy. [ABSTRACT FROM AUTHOR]

Purpose Patients with chronic thromboembolic pulmonary hypertension (CTEPH) display features of systemic inflammation. This study assesses whether high preoperative C-reactive protein (CRP) levels are associated with in-hospital outcomes after pulmonary endarterectomy. Methods This study included 159 patients who underwent pulmonary endarterectomy from 2009 to 2013 (derivation cohort) and 238 patients from 2015 to 2016 (validation cohort) from the French national CTEPH registry. The correlations between pro-inflammatory markers (CRP, interleukins 1 and 6, fibrinogen and leukocytes) and hemodynamics were assessed in the derivation cohort. Pre-, perioperative characteristics and 30-day outcomes (primary endpoint: death or lung transplant or extracorporeal membrane oxygenation need or inotropic or vasopressor need more than 2 days) of patients with high or low CRP levels were compared. Results Median age of the derivation cohort was 63 [52-73] years with 48% of female, 80% in NYHA class III/IV. CRP levels moderately correlated with fibrinogen, interleukin-6 and neutrophils count (r range 0.28-0.47). The validation cohort had similar demographics and disease severity. Patients with high CRP had higher resistance levels and lower cardiac index than those with low CRP in both cohorts. The primary endpoint was reached in 38% (derivation) and 42% (validation) of patients. In multivariable logistic regression analysis, CRP higher than 10 mg/L was associated with the primary endpoint in both the derivation cohort (odd ratio = 2.49 [1.11-5.61], independently of NYHA class IV and aortic clamping duration) and the validation cohort (odd ratio = 1.89 [1.09-3.61], independently of age and aortic clamping duration). Conclusion Preoperative CRP level higher than 10 mg/L is independently associated with adverse early outcomes after pulmonary endarterectomy. [ABSTRACT FROM AUTHOR]

Introduction Malgré les traitements disponibles, le pronostic des patients atteints d’HTAP associée aux connectivites (HTAP-Co) reste particulièrement mauvais comparé aux autres étiologies de l’HTAP. L’étude de phase III Griphon, contrôlée contre placebo ( NCT01106014 ) a inclus 1 156 patients dont 334 atteints d’HTAP-Co. Dans le sous-groupe HTAP-Co, le selexipag a réduit significativement le risque de survenue d’un évènement du critère principal composite de morbi-mortalité de 41 % ( hazard ratio [HR] 0,59 ; IC99 % : 0,37–0,96) jusqu’à la fin du traitement. Les différentes connectivites ayant des physiopathologies et des pronostics différents, nous avons examiné les effets du selexipag versus placebo chez les patients atteints d’HTAP associée à une sclérodermie systémique (HTAP-ScS), un lupus érythémateux systémique (HTAP-LES) ou une connectivite mixte (HTAP-CM). Patients et méthodes Les patients (18–75 ans) ont été randomisés 1:1 dans les groupes placebo ou selexipag. Les HRs (95 % IC) ont été calculés avec un modèle de régression de Cox pour déterminer les effets du selexipag versus placebo sur la morbi-mortalité. Résultats Parmi les 334 patients atteints d’HTAP-Co, 170 présentaient une HTAP-ScS, 82 une PAH-LED et 42 une PAH-CM. Pour 35 patients, le type d’HTAP-Co n’a pas été rapporté, de fait, les données de ces patients n’ont pas été incluses. Dans les 3 sous-groupes d’HTAP-Co, la majorité des patients étaient des femmes (84–99 %) et étaient traités avec un antagoniste du récepteur de l’endothéline, un inhibiteur de la phosphodiestérase de type-5 ou les 2 à l’inclusion (73–83 %). Dans les 3 groupes HTAP-ScS, HTAP-LED, HTAP-CM, l’âge moyen (DS) était 60,0 (10,6), 39,0 (11,3) et 48,0 (14,7) ans respectivement et 65 %, 33 % et 45 % des patients étaient en classe fonctionnelle OMS III, respectivement. Le selexipag a réduit le risque de survenue d’un évènement de morbi-mortalité de 44 % (0,56 ; 0,34–0,91) chez les patients HTAP -ScS, de 34 % (0,66 ; 0,30–1,48) chez les patients HTAP -LED et de 53 % (0,47 ; 0,15–1,48) chez les patients HTAP-CM. L’effet traitement était consistent dans les sous-groupes d’HTAP-Co (un test d’interaction n’indique pas d’hétérogénéité ; p = 0,6737). À la fin de l’étude, 22 patients HTAP-ScS, 7 HTAP-LED et 3 HTAP-CM dans le groupe placebo et 17 HTAP-ScS, 4 HTAP-LED et 8 HTAP-CM dans le groupe selexipag étaient décédés. Les effets indésirables les plus fréquemment associés aux traitements de la voie de la prostacycline ont été observés avec le selexipag chez les patients HTAP-Co (par ex. céphalées, diarrhées, nausées) à la même fréquence que chez les patients avec d’autres étiologies de l’HTAP, et au sein des sous-groupes de HTAP-Co. Conclusion L’étude GRIPHON a inclus la plus importante cohorte de patients HTAP-Co à ce jour. L’effet traitement du selexipag sur le délai de survenue du premier évènement de morbi-mortalité était consistent dans les sous-groupes HTAP-ScS, HTAP-LES et HTAP-CM. Ces données suggèrent que cibler la voie de la prostacycline avec le selexipag est une option thérapeutique efficace pour ces patients difficiles à traiter ( Fig. 1 ). [ABSTRACT FROM AUTHOR]

Introduction et objectifs: L’impact des traitements actuels de l’infection VIH (HAART) et des traitements spécifiques de l’hypertension artérielle pulmonaire (HTAP) sur la sévérité et le pronostic de l’HTAP associée à l’infection VIH (HTAP-VIH) est mal connu. Les objectifs de cette étude étaient de déterminer les facteurs pronostiques au cours l’HTAP-VIH à l’heure des traitements modernes. Matériels et méthodes: Analyse rétrospective des données de tous les patients consécutifs ayant une HTAP-VIH sans autre facteur de risque pour l’HTAP vus dans le Centre National de Référence de l’HTAP entre 10/2000 et 1/2008. Résultats: 77 patients (58 % hommes, âge moyen 41 ans, ancienneté de l’infection VIH 11,1 ans, toxicomanie 36 %). Lors du diagnostic d’HTAP, 81 % des patients recevaient HAART, 79 % avaient des CD4+ >200/mm3 et 49 % une charge virale indétectable. La classe NYHA était : II (22 %), III (69 %) et IV (9 %). La distance de marche médiane au test de marche de 6 minutes (DM6’) était de 375m, et les résistances vasculaires pulmonaires médianes de 689 d.s.cm−5. Tous les patients ont été traités par HAART (quel que soit leur statut VIH) et 50 ont reçu un traitement spécifique de l’HTAP, conduisant à une amélioration de la DM6’ et de l’hémodynamique. Chez les patients ayant reçu HAART sans traitement spécifique de l’HTAP, la DM6’ s’est améliorée mais l’hémodynamique ne s’est pas modifiée. La survie globale était 88 % à 1 an et de 72 % à 3 ans. En analyse multivariée, un index cardiaque > 2,8L/min/m2 et untaux de CD4+ > 200/mm3 étaient des facteurs pronostiques indépendants de survie. Conclusion: Chez les patients HTAP-VIH, un traitement antirétroviral seul (HAART) ne permet pas d’amélioration hémodynamique. Le pronostic des patients HTAP-VIH est essentiellement lié aux taux de CD4+ et à la fonction cardiaque. [Copyright &y& Elsevier]

Introduction et objectifs: L’hypertension artérielle pulmonaire (HTAP) est un facteur indépendant de mortalité au cours de l’infection VIH. Le bosentan, un antagoniste des récepteurs de l’endothéline, semble particulièrement efficace dans l’HTAP associée à l’infection VIH (HTAP-VIH). Nous décrivons les effets à long terme du bosentan administré en première intention à des patients non sélectionnés ayant une HTAP-VIH. Matériels et méthodes: Les données de tous les patients HTAP-VIH consécutifs, en classe fonctionnelle (CF) NYHA II-IV, traités par bosentan en première intention entre 5/2002 et 7/2007 ont été analysées. Le statut VIH, la distance parcourue au test de marche de 6 minutes (DM6’) et les paramètres hémodynamiques mesurés par cathétérisme cardiaque droit ont été évalués avant traitement, après 4 mois puis tous les 6-12 mois. Résultats: 59 patients (63 % hommes, âge moyen 40 ans, 83 % sous HAART, charge virale indétectable chez 51 %, CD4 437±574/mm3). À 4 mois, la DM6’ a augmenté de 358±98 à 435±89m et les résistances vasculaires pulmonaires ont diminué de 737±328 à 476±302 d.s.cm−5. À la dernière évaluation (29±15 mois), la DM6’ et les paramètres hémodynamiques sont restés stables. Chez 10 des 59 patients, les paramètres fonctionnels ethémodynamiques se sont normalisés. À la dernière évaluation, ces 10 patients étaient en CF NYHA I avec une DM6’ de 532±52m. La survie globale était de 93,86 et 66 % à 1, 2 et 3 ans. Le profil de tolérance du bosentan, associé au HAART a été bon, sans impact délétère sur le contrôle du VIH. Conclusion: Ces résultats confirment le bénéfice à long terme du bosentan dans l’HTAP-VIH. Une normalisation hémodynamique, constaté chez des 10 des 59 patients traités, est tout à fait exceptionnelle dans l’HTAP. [Copyright &y& Elsevier]

Abstract: The treatment of pulmonary arterial hypertension aims at counteracting the deleterious effects of vasoconstriction, pulmonary vascular obstruction, and right heart failure. Recent advances in medical therapy (endothelin receptor antagonists, prostacyclin analogs, phosphodiesterase 5 inhibitors) result from a better understanding of the pathophysiologic mechanisms of pulmonary hypertension and in particular of the role of endothelial dysfunction which has for consequence a decreased production of vasodilatory agents (prostacyclin, nitric oxide) and an increased production of vasoconstricting agents (endothelin-1, thromboxane), which also stimulate vascular smooth muscle cell proliferation. These new medications, targeted at correcting endothelial dysfunction, have led to a substantial increase in life expectancy. Unfortunately, none of these medications taken isolately can bring a complete cure of this severe disease. Future developments will be based upon combination of currently used medications, as well as in the design of new molecules targeting additional pathophysiologic mechanisms (serotonin reuptake inhibitors, tyrosine kinase inhibitors). This represents a major challenge for patients suffering from this still severe disease. [Copyright &y& Elsevier]