SUMMARY

• Peripheral edema is a known clinical consequence of pulmonary arterial hypertension (PAH) and worsening PAH and is also a known effect of endothelin receptor antagonists (ERAs).¹
• In the SERAPHIN study in PAH, 45/249 (18.1%) patients receiving placebo, 40/250 (16.0%) patients receiving macitentan 3 mg, and 44/242 (18.2%) patients receiving OPSUMIT reported peripheral edema.¹
• Peripheral edema was reported as an adverse event (AE) in the MUSIC study in idiopathic pulmonary fibrosis, the DUAL-1 and DUAL-2 studies in systemic sclerosis (SSc), the MERIT-1 study in inoperable chronic thromboembolic pulmonary hypertension (CTEPH), the MELODY-1 study in combined pre- and post-capillary pulmonary hypertension (CpcPH), the MAESTRO study in Eisenmenger syndrome, the PORTICO study in portopulmonary hypertension, the A DUE study, and in the OPUS/OrPHeUS registry in patients with PAH newly initiating OPSUMIT.^2-15
• Peripheral edema was reported as an AE of special interest (n/N=3/467) in a real-world study that evaluated the safety and effectiveness of OPSUMIT in patients with PAH.¹⁶
• Additional citations pertaining to this topic are included in the REFERENCES section for your review.^17-21
• Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

CLINICAL DATA

Information From the SERAPHIN Study in PAH

The Study with an Endothelin Receptor Antagonist in Pulmonary arterial Hypertension to Improve cliNical outcome (SERAPHIN) trial was a multicenter, double-blind, randomized, placebo-controlled, event driven phase 3 study to assess the long-term safety and efficacy of OPSUMIT in patients with symptomatic PAH.¹ Patients ≥12 years of age (N=742) were randomized 1:1:1 to receive OPSUMIT, macitentan 3 mg, or placebo once daily. The mean duration of study treatment was 103.9, 99.5, and 85.3 weeks for patients who received OPSUMIT, macitentan 3 mg, and placebo, respectively.¹

In SERAPHIN, peripheral edema was reported with similar incidences across the macitentan and placebo treatment groups.¹ Altogether, 45/249 (18.1%) patients receiving placebo, 40/250 (16%) receiving macitentan 3 mg, and 44/242 (18.2%) receiving OPSUMIT experienced peripheral edema. Furthermore, 2 patients (0.8%) in the placebo group and no patients in the macitentan 3 mg and OPSUMIT groups reported severe peripheral edema.²² The incidence of peripheral edema by severity during SERAPHIN is summarized in Table: Incidence of Peripheral Edema by Severity in SERAPHIN below.

Peripheral Edema AEs by Subgroup

Evaluation of peripheral edema in the PAH population by subgroups (sex, age, World Health Organization [WHO] functional class (FC) at baseline, PAH etiology, clinical signs and symptoms of right heart failure at baseline, PAH therapy at baseline, race, and geographic location) indicated that although the incidences varied across the subgroups, there was little indication of a clinically relevant effect of macitentan on the basis of a difference compared with placebo treatment (macitentan vs placebo) or macitentan dose.²²

In patients with WHO FC I/II at baseline, the incidence of peripheral edema was higher in the OPSUMIT group (22.3%) than in the macitentan 3 mg (11.6%) and placebo (14.6%) groups. However, in patients with WHO FC III/IV at baseline, the incidence of peripheral edema was lower with OPSUMIT (14.0%) compared with macitentan 3 mg (21.4%) and placebo (21.8%).²²

In elderly patients (≥ 65 years), the incidence of peripheral edema was higher in the macitentan groups (30.3% and 25.9% in the macitentan 3 mg and OPSUMIT groups, respectively) than in the placebo group (18.2%). In patients aged 18-64 years, the incidence in the placebo group was similar to that in the elderly patients (18.7%), but in the macitentan groups, the incidence was lower (14.3% and 17.7% with macitentan 3 mg and OPSUMIT, respectively).²²

Information From the MUSIC Study in Idiopathic Pulmonary Fibrosis

The Macitentan USe in an Idiopathic pulmonary fibrosis Clinical (MUSIC) trial was a prospective, randomized, double-blind, multicenter, parallel-group, placebo-controlled phase 2 proof of concept trial. In total, 178 patients were randomized 2:1 to daily OPSUMIT (n=119) or placebo (n=59). The incidence of peripheral edema was higher in the OPSUMIT group (11.8%) than in the placebo group (6.8%).²

Information From the DUAL-1 and DUAL-2 Studies in SSc

DUAL-1 and DUAL-2 were phase 3 prospective, randomized, placebo-controlled, doubleblind, multicenter, parallel-group studies to assess the efficacy, safety, and tolerability of macitentan in patients with ischemic digital ulcers associated with SSc. In DUAL-1, a total of 289 patients were randomized 1:1:1 to receive daily macitentan 3 mg (n=95), OPSUMIT (n=97), or placebo (n=97). Similarly, in DUAL-2, a total of 265 patients were randomized 1:1:1 to receive daily macitentan 3 mg (n=88), OPSUMIT (n=88), or placebo (n=89). The overall incidence of peripheral edema reported in the DUAL-1 and DUAL-2 studies are summarized in Table: Incidence of Peripheral Edema by Severity in DUAL-1 and DUAL-2 below.⁶

Information From Study 201 in Essential Hypertension

Study 201 was a multicenter, randomized, placebo- and active-controlled phase 2 study in 379 patients with essential hypertension. Patients were randomized 1:1:1:1:1 to receive macitentan 0.3 mg (n=63), macitentan 1 mg (n=66), macitentan 3 mg (n=61), OPSUMIT (n=62), enalapril (n=65) or placebo (n=62). In Study 201, no fluid retention or peripheral edema AEs were reported in any of the patients receiving macitentan.²²

Information From MELODY-1

MELODY-1 was a multicenter, double-blind, randomized, placebo-controlled, 12-week, phase 2 study to evaluate the safety and tolerability of OPSUMIT in patients with CpcPH due to left ventricular dysfunction. Sixty-three patients were randomized 1:1 to receive OPSUMIT (n=31) or placebo (n=32) once daily. Eight (25.8%) patients in the macitentan group and 6 (18.8%) in the placebo group had at least 1 AE related to edema and fluid overload.³

Information From MAESTRO

MAESTRO was a multicenter, double-blind, randomized, placebo-controlled, 16-week, phase 3 study to assess the efficacy, safety, and tolerability of macitentan in patients with Eisenmenger syndrome. Two hundred and twenty-six patients were randomized 1:1 to receive OPSUMIT (n=114) or placebo (n=112) once daily. Eight patients (7.0%) in the OPSUMIT group and 6 (5.4%) in the placebo group had at least 1 AE related to edema and fluid overload.⁴

Information From PORTICO

PORTICO was a randomized, double-blind, placebo-controlled, prospective, multicenter, 12week trial to assess the safety and efficacy of macitentan in patients with portopulmonary hypertension. Patients were randomized to OPSUMIT (n=43) or placebo (n=42). The incidence of peripheral edema was higher in the macitentan group (25.6%) than the placebo group (11.9%).⁹

Information From MERIT-1

MERIT-1 was a phase 2, double-blind, randomized, placebo-controlled trial to assess macitentan in 80 patients with CTEPH adjudicated as inoperable. Eighty patients were randomized 1:1 to receive OPSUMIT daily (n=40) or placebo (n=40). The incidence of peripheral edema was higher in the OPSUMIT group (23%) than the placebo group (10%).⁸

Information From A DUE 

A DUE was a phase 3, prospective, multicenter, double-blind, randomized, active-controlled study. This study assessed the safety and efficacy of a once-daily, single tablet fixed-dosing combination of macitentan 10 mg and tadalafil 40 mg (M/T FDC) vs OPSUMIT and tadalafil 40 mg monotherapies in PAH patients, including treatment-naïve and prior ERA or PDE5i monotherapy-treated patients. One hundred eighty-seven patients were randomized to receive single tablet M/T FDC (n=108), OPSUMIT (n=35) or tadalafil (n=44). The incidence of peripheral edema was higher in the M/T FDC group (13.1%, [14/107; 1 patient did not receive any treatment and was not included in the full analysis set]) compared to the OPSUMIT (11.4% [4/35]) and tadalafil (11.4% [5/44]) groups.⁷ 

Information From OPUS/OrPHeUS

The OPUS registry (NCT02126943) and the OrPHeUS chart review (NCT03197688) provided real-world data for patients with PAH newly initiating OPSUMIT.^10,11,14,15

McLaughlin et al (2022)¹⁰ included patients from the OPUS and OrPHeUS registries, which were patients who initiated OPSUMIT from April 2014-June 2020 and October 2013March 2017, respectively. There was a total of 5654 enrolled patients from the OPUS and OrPHeUS registries combined (2670 and 2984 patients from OPUS and OrPHeUS, respectively). Four patients didn’t have follow-up data; therefore, the overall follow-up set was 5650 patients. In OPUS, 283/2667 (10.6%) of patients experienced peripheral edema during the observation period (from initiation of OPSUMIT to the end of study, death, loss of follow-up, consent withdrawal, or date of OPSUMIT discontinuation+30 days). No AE reporting (with the exception of hepatic AEs) was conducted in OrPHeUS due to the retrospective design.

McLaughlin et al (2024)¹³ described the safety of OPSUMIT in patients based on race in the combined OPUS/OrPHeUS dataset. The follow-up set included 752 Black/African American (AA) and 3484 White patients. Based on OPUS safety data (n=355 Black/AA, n=1748 White), 11.8% of Black/AA patients and 10.2% of White patients experienced peripheral edema AEs.  

Melendres-Groves et al (2024)¹² described the safety of OPSUMIT in patients based on ethnicity in the combined OPUS/OrPHeUS dataset. The follow-up set comprised of 517 Hispanic/Latino patients, 3907 not Hispanic/Latino patients, and 185 unknown and 17 missing ethnicity patients. Based on OPUS safety data, 24/274 (8.8%) and 217/1980 (11.0%) Hispanic/Latino and not Hispanic/Latino patients experienced peripheral edema AEs, respectively.

Rahaghi et al (2021)¹¹ described the safety of OPSUMIT in patients with elevated pulmonary capillary wedge pressure (PCWP; >15 mmHg) in the combined OPUS/OrPHeUS dataset. Based on safety data collected only from the OPUS registry (as of June 2020; high PCWP, n=289 [mildly high PCWP, n=156; highly high PCWP, n=133]; investigatorassessed PAH, n=731), peripheral edema was one of the most common AEs that was reported in 11% of patients with high PCWP (mildly high PCWP, 13%; highly high PCWP, 10%) and 12% of patients with investigator-assessed PAH.

Rajagopal et al (2020)¹⁵ described the safety of OPSUMIT in patients with comorbidities enrolled in the OPUS registry. As of August 2019, a total of 2025 patients were evaluated. Overall, the rate of peripheral edema was reported to be 10.2%. Among patients with comorbidities, peripheral edema rates among patients with diabetes, hypertension, anemia, obesity, and renal insufficiency were 11.0%, 11.7%, 11.8%, 9.9% and 10.5%, respectively.

Chin et al (2017)¹⁴ described the safety of OPSUMIT in patients with PAH associated with SSc compared with that in patients with idiopathic PAH (IPAH) enrolled in the OPUS registry. As of January 2017, a total of 191 with PAH-SSc and 577 patients with IPAH were evaluated. In the PAH-SSc vs IPAH groups, ≥1 AE was reported in 63.4% (n=121) vs 55.5% (n=320) of patients and the most common AE included peripheral edema (10.5% vs 8.3%).

Information From Real-World Studies

Jung et al (2023)¹⁶ conducted a prospective, multi-center, real-world, observational study that evaluated the safety and effectiveness of OPSUMIT in adult patients with PAH at 50 medical centers in Korea. Of the 474 enrolled patients, 467 were included in the safety analysis. Of the 467 patients, 344 were female, and the mean (±standard deviation [SD]) age at enrollment was 48.5 (±15.8) years. Overall, 3 (0.64%) patients reported peripheral edema (considered as an AE of special interest) in this study.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, Derwent^® (and/or other resources, including internal/external databases) was conducted on 15 October 2024.