Safety and tolerability of macitentan in the management of pulmonary arterial hypertension: an update

Figures & data

Figure 1 The endothelin pathway. Endothelin-1 and the endothelin receptor pathway. Dual endothelin receptor antagonists, such as macitentan, block the binding of endothelin-1 to both the ET_A and ET_B receptor and block the downstream vasoconstricting effects. Reproduced from Lai YC, Potoka KC, Champion HC, et al. Pulmonary arterial hypertension: the clinical syndrome, Circulation Research, 115, 1, 115–130, https://www.ahajournals.org/.¹⁵

Abbreviations: ECE, endothelin-converting enzymes; ET, endothelin.

Table 1 Summary of clinical trials

Author	Year	Trial Acronym	Patient Population	Size	Intervention (number of patients)	Duration	Primary outcome	Secondary outcome(s)
Raghu^Citation24	2013	MUSIC	IPF	178	10 mg macitentan daily (119) vs placebo (59)	12 months	Change in FVC	Time to IPF worsening or death
								Safety and tolerability of macitentan
Pulido^Citation5	2013	SERAPHIN	PAH	742	Placebo (250) vs 3 mg macitentan daily (250) vs 10 mg macitentan daily (242)	36 months	First event related to PAH (worsening PAH, initiation of IV or SC prostanoid therapy, lung transplant, atrial septostomy) or death	Change in 6MWD distance at month 6
								Percentage of patients with improvement in WHO functional class at month 6
								Death due to PAH or hospitalization for PAH
								Death from any cause
Ghofrani^Citation30	2017	MERIT-1	Inoperable CTEPH	80	10 mg macitentan daily (40) vs placebo (40)	24 weeks	Resting PVR at week 16 (as a percetage of baseline PVR)	Change in 6MWD
								Change in Borg dyspnea score obtained after 6MWT
								Proportion of patients with worsening WHO functional class
Vachiery^Citation29	2018	MELODY-1	PH from left heart disease	63	10 mg macitentan daily (31) vs placebo (32)	12 weeks	Composite of significant fluid retention or worsening NYHA functional class	Changes in NT-proBNP
								Changes in hemodynamics
Gatzoulis^Citation33	2019	MAESTRO	PH from Eisenmenger Syndrome	226	10 mg macitentan (114) daily vs placebo (112)	16 weeks	6MWD	Change in WHO functional class
								Change in NT-proBNP
								Change in PVR in hemodynamic substudy

Abbreviations: IPF, idiopathic pulmonary fibrosis; FVC, forced vital capacity; PAH, pulmonary arterial hypertension; IV, intravenous; SC, subcutaneous; 6MWD, six-minute walk distance; WHO, world health organization; CTEPH, chronic thromboembolic pulmonary hypertension; PVR, pulmonary vascular resistance; PH, pulmonary hypertension; NYHA, New York Heart Association; NT proBNP, N terminal pro-brain natriuretic peptide.

Figure 2 Effect of macitentan on PAH-related hospitalizations. The effect of macitentan 10 mg daily, 3 mg daily, and placebo on the rate of hospitalization due to pulmonary arterial hypertension (PAH). Macitentan at 10 mg daily showed a 49.8% reduction in PAH-related hospitalizations compared to placebo. Reprinted from JACC Heart Fail, 3, 1, Channick RN, Delcroix M, Ghofrani HA, et al, Effect of macitentan on hospitalizations, 1–8, Copyright (2015), with permission from Elsevier.²⁵

Figure 3 Time to significant decline in SF-36 score for macitentan (10 mg, 3 mg) vs placebo. Time to a significant decline in the SF-36 COMPONENT score. Overall, the 10 mg macitentan dose and 3 mg macitentan dose both significantly reduced the risk of a meaningful decline in the SF-36 scores until the end of treatment compared to placebo: Panel A displays the meaningful decline in the physical component score, Panel B depicts the meaningful decline in the mental component score. Reprinted from Chest, 151, 1, Mehta S, Sastry BKS, Souza R, et al, Macitentan improves health-related quality of life for patients with pulmonary arterial hypertension, 106–118, Copyright (2017), with permission from Elsevier.²⁷

Figure 4 Adverse events, abnormalities in liver function tests and hemoglobin. Adverse events in the placebo, 3 mg, and 10 mg arms in the SERAPHIN trial, as well as rates of liver function abnormalities and anemia. From New England Journal of Medicine, Pulido T, Adzerikho I, Channick RN, et al, Macitentan and morbidity and mortality in pulmonary arterial hypertension, 369, 9, 809–818. Copyright © (2013) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.⁵

Figure 5 Rates of adverse events and liver function abnormalities with the use of macitentan in a real-world setting. Data from the OPUS registry evaluating adverse events and liver function test abnormalities with the use of 10 mg daily of macitentan in a real-world setting. Reprinted from The Journal of Heart and Lung Transplantation, 36, 4, Kim NH, Bergmark BA, Zelniker TA, et al, OPUS registry: safety and tolerability of macitentan in a real-world setting, S20-S21, Copyright (2017), with permission from Elsevier.⁴⁵

Lai Y-C, Potoka KC, Champion HC, Mora AL, Gladwin MT. Pulmonary arterial hypertension: the clinical syndrome. Circ Res. 2014;115:115–130. doi:10.1161/CIRCRESAHA.115.30114624951762

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Raghu G, Million-Rousseau R, Morganti A, Perchenet L, Behr J. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J. 2013;42:1622–1632. doi:10.1183/09031936.0010461223682110

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Pulido T, Adzerikho I, Channick RN, et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013;369:809–818. doi:10.1056/NEJMoa121391723984728

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Ghofrani H-A, Casarin A, Ely EW, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med. 2017;5:785–794. doi:10.1016/S2213-2600(17)30234-528919201

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Vachiéry J-L, Delcroix M, Al-Hiti H, et al. Macitentan in pulmonary hypertension due to left ventricular dysfunction. Eur Respir J. 2018;51:1701886. doi:10.1183/13993003.01886-201729437943

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Gatzoulis MA, Landzberg M, Beghetti M, et al. Evaluation of macitentan in patients with Eisenmenger syndrome. Circulation. 2019;139:51–63. doi:10.1161/CIRCULATIONAHA.118.03357530586694

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Channick RN, Delcroix M, Ghofrani HA, et al. Effect of macitentan on hospitalizations. JACC Heart Fail. 2015;3:1–8. doi:10.1016/j.jchf.2014.07.01325457902

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Mehta S, Sastry BKS, Souza R, et al. Macitentan improves health-related quality of life for patients with pulmonary arterial hypertension. Chest. 2017;151:106–118. doi:10.1016/j.chest.2016.08.147327671974

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Kim NH, Bergmark BA, Zelniker TA, et al. OPUS registry: safety and tolerability of macitentan in a real-world setting. J Heart Lung Transplant. 2017;36:S20–S21. doi:10.1016/j.healun.2017.06.015

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