Contemporary Treatment of Pulmonary Arterial Hypertension: A US Perspective.

Pulmonary arterial hypertension (PAH) is a complex fatal condition which requires aggressive treatment with close monitoring. Significant progress has been made over the last three decades in the treatment of PAH but despite this progress, survival has remained unacceptably low. In the quest to improve survival, therapeutic interventions play a central role. In the last few years, there have been remarkable attempts to identify novel treatments. Finally, we have had a breakthrough with the discovery of the fourth treatment pathway in PAH. Activin signaling inhibition distinguishes itself as a potential antiproliferative intervention as opposed to the traditional therapies which mediate their effect primarily by vasodilatation. With this novel treatment pathway, we stand at an important milestone with an exciting future ahead and the natural question of when to utilize Activin signaling inhibitor (ASI) for the treatment of PAH. In this state-of-the-art review, we focus on the placement of this novel agent in the PAH treatment paradigm based on the available evidence, with special focus on the US patient population. This review also provides an expert opinion of the current treatment algorithm on important subgroups of patients with comorbidities from the US perspective.

Multidisciplinary Approach to Chronic Thromboembolic Pulmonary Hypertension: Role of Radiologists.

Management of chronic thromboembolic pulmonary hypertension (CTEPH) should be determined by a multidisciplinary team, ideally at a specialized CTEPH referral center. Radiologists contribute to this multidisciplinary process by helping to confirm the diagnosis of CTEPH and delineating the extent of disease, both of which help determine a treatment decision. Preoperative assessment of CTEPH usually employs multiple imaging modalities, including ventilation-perfusion (V/Q) scanning, echocardiography, CT pulmonary angiography (CTPA), and right heart catheterization with pulmonary angiography. Accurate diagnosis or exclusion of CTEPH at imaging is imperative, as this remains the only form of pulmonary hypertension that is curative with surgery. Unfortunately, CTEPH is often misdiagnosed at CTPA, which can be due to technical factors, patient-related factors, radiologist-related factors, as well as a host of disease mimics including acute pulmonary embolism, in situ thrombus, vasculitis, pulmonary artery sarcoma, and fibrosing mediastinitis. Although V/Q scanning is thought to be substantially more sensitive for CTEPH compared with CTPA, this is likely due to lack of recognition of CTEPH findings rather than a modality limitation. Preoperative evaluation for pulmonary thromboendarterectomy (PTE) includes assessment of technical operability and surgical risk stratification. While the definitive therapy for CTEPH is PTE, other minimally invasive or noninvasive therapies also lead to clinical improvements including greater survival. Complications of PTE that can be identified at postoperative imaging include infection, reperfusion edema or injury, pulmonary hemorrhage, pericardial effusion or hemopericardium, and rethrombosis. ©RSNA, 2022 Online supplemental material is available for this article.

Abnormal pulmonary perfusion heterogeneity in patients with Fontan circulation and pulmonary arterial hypertension.

KEY POINTS: The distribution of pulmonary perfusion is affected by gravity, vascular branching structure and active regulatory mechanisms, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. We evaluated pulmonary perfusion in patients who had undergone Fontan procedure, patients with pulmonary arterial hypertension (PAH) and two groups of controls using a proton magnetic resonance imaging technique, arterial spin labelling to measure perfusion. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Gravitational gradients were similar between all groups, but heterogeneity was significantly increased in both patient groups compared to controls and persisted after removing contributions from large blood vessels and gravitational gradients. Patients with Fontan physiology and patients with PAH have increased pulmonary perfusion heterogeneity that is not explainable by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects vascular remodelling in PAH and possibly in Fontan physiology. ABSTRACT: Many factors affect the distribution of pulmonary perfusion, which may be disrupted by cardiopulmonary disease, but this is not well studied, particularly in rare conditions. An example is following the Fontan procedure, where pulmonary perfusion is passive, and heterogeneity may be increased because of the underlying pathophysiology leading to Fontan palliation, remodelling, or increased gravitational gradients from low flow. Another is pulmonary arterial hypertension (PAH), where gravitational gradients may be reduced secondary to high pressures, but remodelling may increase perfusion heterogeneity. We evaluated regional pulmonary perfusion in Fontan patients (n = 5), healthy young controls (Fontan control, n = 5), patients with PAH (n = 6) and healthy older controls (PAH control) using proton magnetic resonance imaging. Regional perfusion was measured using arterial spin labelling. Heterogeneity was assessed by the relative dispersion (SD/mean) and gravitational gradients. Mean perfusion was similar (Fontan = 2.50 ± 1.02 ml min-1  ml-1 ; Fontan control = 3.09 ± 0.58, PAH = 3.63 ± 1.95; PAH control = 3.98 ± 0.91, P = 0.26), and the slopes of gravitational gradients were not different (Fontan = -0.23 ± 0.09 ml min-1  ml-1  cm-1 ; Fontan control = -0.29 ± 0.23, PAH = -0.27 ± 0.09, PAH control = -0.25 ± 0.18, P = 0.91) between groups. Perfusion relative dispersion was greater in both Fontan and PAH than controls (Fontan = 1.46 ± 0.18; Fontan control = 0.99 ± 0.21, P = 0.005; PAH = 1.22 ± 0.27, PAH control = 0.91 ± 0.12, P = 0.02) but similar between patient groups (P = 0.13). These findings persisted after removing contributions from large blood vessels and gravitational gradients (all P < 0.05). We conclude that patients with Fontan physiology and PAH have increased pulmonary perfusion heterogeneity that is not explained by differences in mean perfusion, gravitational gradients, or large vessel anatomy. This probably reflects the effects of remodelling in PAH and possibly in Fontan physiology.

TRPC6, a therapeutic target for pulmonary hypertension.

Idiopathic pulmonary arterial hypertension (PAH) is a fatal and progressive disease. Sustained vasoconstriction due to pulmonary arterial smooth muscle cell (PASMC) contraction and concentric arterial remodeling due partially to PASMC proliferation are the major causes for increased pulmonary vascular resistance and increased pulmonary arterial pressure in patients with precapillary pulmonary hypertension (PH) including PAH and PH due to respiratory diseases or hypoxemia. We and others observed upregulation of TRPC6 channels in PASMCs from patients with PAH. A rise in cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC triggers PASMC contraction and vasoconstriction, while Ca2+-dependent activation of PI3K/AKT/mTOR pathway is a pivotal signaling cascade for cell proliferation and gene expression. Despite evidence supporting a pathological role of TRPC6, no selective and orally bioavailable TRPC6 antagonist has yet been developed and tested for treatment of PAH or PH. In this study, we sought to investigate whether block of receptor-operated Ca2+ channels using a nonselective blocker of cation channels, 2-aminoethyl diphenylborinate (2-APB, administered intraperitoneally) and a selective blocker of TRPC6, BI-749327 (administered orally) can reverse established PH in mice. The results from the study show that intrapulmonary application of 2-APB (40 µM) or BI-749327 (3-10 µM) significantly and reversibly inhibited acute alveolar hypoxia-induced pulmonary vasoconstriction. Intraperitoneal injection of 2-APB (1 mg/kg per day) significantly attenuated the development of PH and partially reversed established PH in mice. Oral gavage of BI-749327 (30 mg/kg, every day, for 2 wk) reversed established PH by ∼50% via regression of pulmonary vascular remodeling. Furthermore, 2-APB and BI-749327 both significantly inhibited PDGF- and serum-mediated phosphorylation of AKT and mTOR in PASMC. In summary, the receptor-operated and mechanosensitive TRPC6 channel is a good target for developing novel treatment for PAH/PH. BI-749327, a selective TRPC6 blocker, is potentially a novel and effective drug for treating PAH and PH due to respiratory diseases or hypoxemia.

ERS statement on chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels <500 µm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/perfusion lung scan shows mismatched perfusion defects, and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions.This statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow-up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH.It represents the first collaboration of the European Respiratory Society, the International CTEPH Association and the European Reference Network-Lung in the pulmonary hypertension domain. The statement summarises current knowledge, but does not make formal recommendations for clinical practice.

Patient Positioning Guidelines for Gastrointestinal Endoscopic Procedures.

Patient positioning during gastrointestinal endoscopic procedures has received minimal attention compared with surgical procedures performed in the surgical setting. However, prolonged endoscopic interventions on patients and the increasing requirement for general anesthesia have changed to need for patient positioning guidelines. The objective of this study was to test whether patient positioning guidelines for surgical procedures in surgical suites are suitable for gastrointestinal endoscopic procedures without negatively impacting safety and procedure duration. This was an observational feasibility study with volunteers of different body mass index categories. Volunteers were positioned in supine, lateral, and prone positions on an operating table and thereafter on an endoscopy stretcher and asked for comfort levels. Except for arm and head positioning in lateral and prone positions, it was possible to replicate the patient positioning guidelines. Alternative options were explored for the positioning of arms and head to optimize oral access. Besides minor adjustments, we were able to replicate the positioning guidelines and adhere to pressure and nerve injury prevention guidelines. Concept endoscopic patient positioning guidelines were developed. It is recommended to review the "swimmer's" position. Endoscopic patient positioning guidelines should become part of the National Practice Standards and education curriculum of endoscopy nurses.

Chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic PH leading to right heart failure and death. Lung ventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In the case of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm and define the pulmonary vascular involvement and prior to making a treatment decision. PH is confirmed with right heart catheterisation, which is also necessary for treatment determination. In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. For technically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based on the CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced with this challenging but potentially effective and complementary intervention.

Ramelteon for Prevention of Postoperative Delirium: A Randomized Controlled Trial in Patients Undergoing Elective Pulmonary Thromboendarterectomy.

OBJECTIVES: To assess the efficacy of ramelteon in preventing delirium, an acute neuropsychiatric condition associated with increased morbidity and mortality, in the perioperative, ICU setting. DESIGN: Parallel-arm, randomized, double-blinded, placebo-controlled trial. SETTING: Academic medical center in La Jolla, California. PATIENTS: Patients greater than or equal to 18 years undergoing elective pulmonary thromboendarterectomy. INTERVENTIONS: Ramelteon 8 mg or matching placebo starting the night prior to surgery and for a maximum of six nights while in the ICU. MEASUREMENTS AND MAIN RESULTS: Incident delirium was measured twice daily using the Confusion Assessment Method-ICU. The safety outcome was coma-free days assessed by the Richmond Agitation-Sedation Scale. One-hundred twenty participants were enrolled and analysis completed in 117. Delirium occurred in 22 of 58 patients allocated to placebo versus 19 of 59 allocated to ramelteon (relative risk, 0.8; 95% CI, 0.5-1.4; p = 0.516). Delirium duration, as assessed by the number of delirium-free days was also similar in both groups (placebo median 2 d [interquartile range, 2-3 d] vs ramelteon 3 d [2-5 d]; p = 0.181). Coma-free days was also similar between groups (placebo median 2 d [interquartile range, 1-3 d] vs ramelteon 3 d [2-4 d]; p = 0.210). We found no difference in ICU length of stay (median 4 d [interquartile range, 3-5 d] vs 4 d [3-6 d]; p = 0.349), or in-hospital mortality (four vs three deaths; relative risk ratio, 0.7; 95% CI, 0.2-3.2; p = 0.717), all placebo versus ramelteon, respectively. CONCLUSIONS: Ramelteon 8 mg did not prevent postoperative delirium in patients admitted for elective cardiac surgery.

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.)

Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2).

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit-risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit-risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year.

Advances in the management of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable form of pulmonary hypertension with pulmonary thromboendarterectomy surgery, has been the focus of significant medical advances. In addition to new imaging modalities that are now used to help recognize and diagnose CTEPH, additional treatment options have emerged for inoperable cases. These include a newly approved medical therapy for inoperable disease or persistent/recurrent CTEPH as well as percutaneous balloon angioplasty of the pulmonary arteries. In this article, we summarize these recent advances in the field and review the related literature.

Two formulations of epoprostenol sodium in the treatment of pulmonary arterial hypertension: EPITOME-1 (epoprostenol for injection in pulmonary arterial hypertension), a phase IV, open-label, randomized study.

BACKGROUND: Epoprostenol sodium with arginine-mannitol excipients (epoprostenol AM; Veletri [Actelion Pharmaceuticals Ltd, Allschwil, Switzerland]) and epoprostenol sodium with glycine-mannitol excipients (epoprostenol GM; Flolan [GlaxoSmithKline, Triangle Park, NC]) are intravenous treatments for pulmonary arterial hypertension (PAH). Epoprostenol AM contains different inactive excipients, resulting in greater stability at room temperature compared with epoprostenol GM. METHODS: In this prospective, multicenter, open-label, randomized, phase IV exploratory study, epoprostenol-naïve patients in need of injectable prostanoid therapy were randomized 2:1 to open-label epoprostenol AM or epoprostenol GM. The study period was 28 days, followed by a 30-day safety follow-up. Study aims were to descriptively compare the safety, tolerability, drug metabolite levels, and treatment effects of epoprostenol AM and epoprostenol GM in PAH. Statistical analysis was descriptive only because of the exploratory nature of the study. RESULTS: Thirty patients with PAH (18-70 years, 24 women, 20 idiopathic PAH) were randomized to epoprostenol AM (n = 20) or epoprostenol GM (n = 10). Most frequently reported adverse events included jaw pain, headache, nausea, and flushing. Two deaths occurred during the study period, and 1 death occurred during the 30-day safety follow-up period, all in patients receiving epoprostenol AM. All deaths were classified by the treating physician as unrelated to epoprostenol AM. The median (range) change from baseline to day 28 in 6-minute walk distance was 36 m (-127 to 210 m) and 49 m (-44 to 110 m) for the epoprostenol AM and epoprostenol GM groups, respectively. CONCLUSIONS: In this randomized clinical study of epoprostenol AM in PAH, use of this novel preparation with greater room temperature stability was well tolerated.

Echocardiographic estimation of pulmonary vascular resistance in chronic thromboembolic pulmonary hypertension: utility of right heart Doppler measurements.

UNLABELLED: The ratio of tricuspid regurgitation velocity divided by the velocity-time integral of right ventricular outflow tract pulsed-wave Doppler tracing (TRV/VTI(RVOT) ) has been used to estimate pulmonary vascular resistance (PVR). However, this method has not been validated in chronic thromboembolic pulmonary hypertension (CTEPH). We assessed the utility of TRV/VTI(RVOT) in patients with CTEPH and PVR from 2 to 20 WU. All had right heart catheterization (RHC) within 2 days of echocardiography. TRV/VTI(RVOT) was calculated and RHC-derived pressures, PVR, and cardiac outputs were recorded. Mean pulmonary artery pressure was 47 ± 12 mmHg, cardiac output: 4.2 ± 1.1 L/min, PVR: 9 ± 4 WU, right atrial pressure: 12 ± 6 mmHg. Mean VTI(RVOT) was 13 ± 5 cm; mean TRV was 4.2 ± 0.8 m/s, mean tricuspid regurgitation severity was 2.5 ± 0.8 (1 = trace, 2 = mild, 3 = moderate, 4 = severe). Regression analysis demonstrated a correlation between RHC PVR and TRV/VTI(RVOT) : PVR = 19.4 × (TRV/VTI(RVOT) ) + 2.4 (r = 0.74, P < 0.001). However, Bland-Altman analysis found a poor degree of agreement between echo-derived PVR and RHC PVR. We also studied 28 patients with non-CTEPH pulmonary hypertension. Similar analysis revealed a regression equation of PVR = 20.1 × (TRV/VTIR(RVOT) ) + 0.3 (r = 0.57, P < 0.01). CONCLUSION: TRV/VTI(RVOT) is only marginally useful for estimating PVR in CTEPH (r = 0.74). Moreover, the regression equation in CTEPH differs significantly from previous studies in pulmonary hypertension. Reasons for this may include the markedly elevated PVR levels in this population and specific effects on VTI(RVOT) from CTEPH.

[Chronic thromboembolic pulmonary hypertension]. / Kronik tromboembolik pulmoner hipertansiyon.

Since the last World Symposium on Pulmonary Hypertension in 2008, we have witnessed numerous and exciting developments in chronic thromboembolic pulmonary hypertension (CTEPH). Emerging clinical data and advances in technology have led to reinforcing and updated guidance on diagnostic approaches to pulmonary hypertension, guidelines that we hope will lead to better recognition and more timely diagnosis of CTEPH. We have new data on treatment practices across international boundaries as well as long-term outcomes for CTEPH patients treated with or without pulmonary endarterectomy. Furthermore, we have expanded data on alternative treatment options for select CTEPH patients, including data from multiple clinical trials of medical therapy, including 1 recent pivotal trial, and compelling case series of percutaneous pulmonary angioplasty. Lastly, we have garnered more experience, and on a larger international scale, with pulmonary endarterectomy, which is the treatment of choice for operable CTEPH. This report overviews and highlights these important interval developments as deliberated among our task force of CTEPH experts and presented at the 2013 World Symposium on Pulmonary Hypertension in Nice, France. (J Am Coil Cardiol 2013;62:D92-9) ©2013 by the American College of Cardiology Foundation.

Macitentan in Pulmonary Arterial Hypertension Associated with Connective Tissue Disease (CTD-PAH): Real-World Evidence from the Combined OPUS/OrPHeUS Dataset.

INTRODUCTION: Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. METHODS: OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014-June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013-March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). RESULTS: The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan-Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan-Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). CONCLUSIONS: Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. TRIAL REGISTRATION: OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www. CLINICALTRIALS: gov Graphical abstract available for this article.

Disease characteristics, treatments, and outcomes of patients with pulmonary arterial hypertension treated with selexipag in real-world settings from the SPHERE registry (SelexiPag: tHe usErs dRug rEgistry).

BACKGROUND: Selexipag is an oral prostacyclin receptor agonist, indicated for pulmonary arterial hypertension to delay disease progression and reduce the risk of pulmonary arterial hypertension-related hospitalization. SelexiPag: tHe usErs dRug rEgistry (NCT03278002) was a US-based, prospective, real-world registry of selexipag-treated patients. METHODS: Adults with pulmonary hypertension (enrolled 2016-2020) prescribed selexipag were followed for ≤18 months, with data collected at routine clinic visits. Patients were defined as newly or previously initiated if they had started selexipag ≤60 days or >60 days, respectively, before enrollment. RESULTS: The registry included 829 patients (430 newly initiated, 399 previously initiated; 759 with pulmonary arterial hypertension), of whom 55.6% were World Health Organization functional class (FC) 3/4; 57.3% were intermediate or high risk per Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) 2.0. In patients with pulmonary arterial hypertension, 18-month discontinuation rates for adverse events were 22.0%, 32.0%, and 11.9%, and 18-month survival rates were 89.4%, 84.2%, and 94.5% in the overall, newly, and previously initiated patient populations, respectively. From baseline to month 18, most patients had stable or improved FC and stable or improved REVEAL 2.0 risk category status. Discontinuation for adverse events, hospitalization, and survival were similar regardless of patients' individually tolerated selexipag maintenance dose. No new safety signals were identified. CONCLUSIONS: In this real-world analysis of patients initiating selexipag, most patients had stable or improved FC and REVEAL 2.0 risk category. Similar to the GRIPHON trial, outcomes with selexipag in this real-world study were comparable across maintenance dose strata, with no new safety signals.

Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Macitentan is beneficial for long-term treatment of pulmonary arterial hypertension. The microvasculopathy of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension are similar. METHODS: The phase 2, double-blind, randomised, placebo-controlled MERIT-1 trial assessed macitentan in 80 patients with CTEPH adjudicated as inoperable. Patients identified as WHO functional class II-IV with a pulmonary vascular resistance (PVR) of at least 400 dyn·s/cm5 and a walk distance of 150-450 m in 6 min were randomly assigned (1:1), via an interactive voice/web response system, to receive oral macitentan (10 mg once a day) or placebo. Treatment with phosphodiesterase type-5 inhibitors and oral or inhaled prostanoids was permitted for WHO functional class III/IV patients. The primary endpoint was resting PVR at week 16, expressed as percentage of PVR measured at baseline. Analyses were done in all patients who were randomly assigned to treatment; safety analyses were done in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02021292. FINDINGS: Between April 3, 2014, and March 17, 2016, we screened 186 patients for eligibility at 48 hospitals across 20 countries. Of these, 80 patients in 36 hospitals were randomly assigned to treatment (40 patients to macitentan, 40 patients to placebo). At week 16, geometric mean PVR decreased to 71·5% of baseline in the macitentan group and to 87·6% in the placebo group (geometric means ratio 0·81, 95% CI 0·70-0·95, p=0·0098). The most common adverse events in the macitentan group were peripheral oedema (9 [23%] of 40 patients) and decreased haemoglobin (6 [15%]). INTERPRETATION: In MERIT-1, macitentan significantly improved PVR in patients with inoperable CTEPH and was well tolerated. FUNDING: Actelion Pharmaceuticals Ltd.