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The Patient with Non-Group 2 Pulmonary Hypertension
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Sophia Anastasia Mouratoglou, George Giannakoulas
Macitentan is a tissue-targeting endothelin receptor antagonist characterized by high lipophilicity. The safety and efficacy of macitentan were examined in the SERAPHIN trial, the first event-driven randomized, controlled trial in PAH.51 Macitentan 10 mg administered once daily achieved reduction of the primary composite endpoint of death, atrial septostomy, lung transplantation, initiation of treatment with IV or subcutaneous prostanoids, or worsening of PAH. The favorable effects were also seen in patients under sequential combination therapy, to whom macitentan was added on their previous PAH treatment (mainly PDE-5 inhibitor).51
Understanding the role of co-morbidities in interstitial lung diseases
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
Adrian Shifren, Tonya Russell, Adam L Anderson, Steven D Nathan
There are no clear-cut data at this time for the treatment of PH in IPF, and many of the clinical trials using PH therapies in IPF patients have not been specifically directed towards patients with PH. Clinical trials with bosentan (endothelin receptor antagonist) or sildenafil (phosphodiesterase inhibitor) have shown no benefit, although there may be some improvement in exercise tolerance in IPF patients with right ventricular dysfunction with sildenafil (54,55). In the case of ambrisentan, the trial was terminated early due to lack of efficacy (47). Macitentan, another endothelin receptor antagonist, also showed no benefit on mortality or disease progression (56). The RISE-IIP study of riociguat targeted patients with PH due to any of the idiopathic interstitial pneumonias (unpublished data). This study was stopped early for apparent increased mortality and adverse events in the treatment arm. The 2015 updated American Thoracic Society recommendations give a conditional recommendation against the use of all of these medications in IPF (57). Whether or not there is a specific phenotype of patients with PH due to ILD who might benefit from therapy remains to be determined. There does appear to be a very small subgroup of patients with hemodynamic profiles similar to those patients with WHO group 1 PAH. However, if there is any consideration to treating these patients, it should be done under the guidance of an expert centre with adequate experience in treating patients with ILD with or without PH.
Pulmonary hypertension: Hemodynamic assessment and response to vasodilators
Published in Debabrata Mukherjee, Eric R. Bates, Marco Roffi, Richard A. Lange, David J. Moliterno, Nadia M. Whitehead, Cardiovascular Catheterization and Intervention, 2017
Myung H. Park, Vallerie V. Mclaughlin
Macitentan is a dual ETA and ETB endothelin receptor blocker designed to have enhanced tissue penetration, mainly due to an increased proportion of the nonionized form of the molecule improving its ability to cross the lipophilic cell membranes. Macitentan was well-tolerated in a Phase II study among healthy volunteers demonstrating dose-dependent pharmacokinetics. The pivotal Phase III Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) is the first clinical trial in PAH that defined morbidity and mortality as the primary endpoint. This double-blind placebo-controlled study enrolled 742 patients within 180 participating centers in over 40 countries. Patients were randomized to receive placebo or macitanten (10 mg once a day or 3 mg once a day). Most of the patients were classified as New York Heart Association (NYHA) FC II or III (97%) with idiopathic PAH or PAH due to CTD (87%). Baseline hemodynamics were consistent with severe PH with mean PAP 55 mmHg, CI 2.3 L/min/m2, and PVR 12.5 Wood units. The majority of patients were on background therapy, most of which was sildenafil (64%). The mean study duration of treatment was 85 weeks.
Advances in the available non-biological pharmacotherapy prevention and treatment of acute mountain sickness and high altitude cerebral and pulmonary oedema
Published in Expert Opinion on Pharmacotherapy, 2018
K.E. Joyce, S.J.E. Lucas, C.H.E. Imray, G.M Balanos, A. D. Wright
Macitentan is an ETA antagonist indicated for the treatment of pulmonary arterial hypertension (PAH) [141]. Macitentan improves PAP and exercise capacity, so may attenuate the development of altitude illnesses [142,143]. Due to the effects of altitude and the associated hypobaric hypoxic conditions that elicit a disruption in the vasoregulatory processes and promote vasoconstriction, caution should be taken with drugs that may attenuate the vasoconstriction response and favorably affect PAP (see below). The vasoregulatory changes and vascular characteristic changes (reduced capillary density and diameter) induced by hypoxia appear to be attenuated with macitentan in healthy individuals in hypobaric hypoxic conditions [142]. Thus, macitentan could attenuate the development of altitude illnesses by improving capillary blood flow, and microcirculation [142], and attenuating the hypoxia-induced rise in PAPs.
Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients
Published in Current Medical Research and Opinion, 2020
Nobuhiro Tahara, Hiroaki Dobashi, Keiichi Fukuda, Masanori Funauchi, Masaru Hatano, Satoshi Ikeda, Shuji Joho, Yasuki Kihara, Takahisa Kondo, Masakazu Matsushita, Tohru Minamino, Norifumi Nakanishi, Yoshiaki Okano, Yukio Ozaki, Tsutomu Saji, Satoshi Sakai, Nobuhiro Tanabe, Hiroshi Watanabe, Hidehiro Yamada, Koichiro Yoshioka, Motonori Hatta, Shigetake Sasayama
Macitentan at a once-daily dose of 10 mg was well tolerated in Japanese patients with PAH. Except for 1 patient who died due to pulmonary embolism on day 340 judged to be unrelated to study drug, macitentan therapy was not discontinued in any patient for safety-related reasons. Headache in 10 patients (33.3%), flushing in 8 patients (26.7%), and anemia in 4 patients (13.3%) were observed as adverse events related to macitentan during the long-term treatment (Table 3). Liver enzyme levels and hemoglobin levels remained unchanged through the entire study period (Figure 2(A,B)). No clinically significant changes from baseline were found in heart rate, blood pressure, or 12-lead electrocardiographic parameters.
An update on current and emerging treatments for pulmonary arterial hypertension in childhood and adolescence
Published in Expert Review of Respiratory Medicine, 2019
Julie Wacker, Robert Weintraub, Maurice Beghetti
Interestingly, a recent randomized controlled study in adult patients with Eisenmenger syndrome (MAESTRO [Clinical Study to Evaluate the Effects of Macitentan on Exercise Capacity in Subjects With Eisenmenger Syndrome]) showed no safety concerns regarding macitentan, but was neutral in its primary endpoint of 6 MWD (largely due to an unexplained improved 6 MWD observed in the placebo arm). A phase 3 trial on the use of macitentan in children aged 2–17 years with PAH is ongoing (TOMORROW [A Study to Assess Whether Macitentan Delays Disease Progressio in Children With Pulmonary Arterial Hypertension]; NCT02932410).