New England Journal of Medicine AUGUST 29, 2013

Macitentan and Morbidity and Mortality in Pulmonary Arterial Hypertension

Pulido T, Adzerikho I, Channick RN, et al.

Bottom Line

In the SERAPHIN trial, the dual endothelin receptor antagonist macitentan significantly reduced the risk of morbidity and mortality in patients with symptomatic pulmonary arterial hypertension compared with placebo.

Key Findings

1. The primary endpoint (composite of death, atrial septostomy, lung transplantation, initiation of intravenous/subcutaneous prostanoids, or worsening of PAH) occurred in 46.4% of patients in the placebo group, compared to 38.0% in the 3 mg macitentan group (HR 0.70; p=0.01) and 31.4% in the 10 mg macitentan group (HR 0.55; p<0.001).

2. The treatment effect was primarily driven by a reduction in worsening of PAH (24.4% in the 10 mg group vs 37.2% in the placebo group).

3. The risk of PAH-related hospitalization or death was reduced by 50% in the 10 mg macitentan group compared to placebo (p<0.001).

4. All-cause mortality was similar across all groups, as the trial was not powered to detect a mortality benefit.

5. Macitentan demonstrated a safety profile generally comparable to placebo, though nasopharyngitis, headache, and anemia were reported more frequently with the active drug.

Study Design

Design

RCT

Double-Blind

Sample

742

Patients

Duration

115 wk

Median

Setting

Multicenter, Global

Population Adults (>=12 years) with symptomatic pulmonary arterial hypertension (WHO functional class II, III, or IV).

Intervention Oral macitentan (3 mg or 10 mg) once daily.

Comparator Placebo once daily.

Outcome Time from initiation of treatment to the first morbidity or mortality event (death, atrial septostomy, lung transplantation, initiation of intravenous/subcutaneous prostanoids, or worsening of PAH).

Study Limitations

• The study was not specifically powered to detect an effect on all-cause mortality as a stand-alone endpoint.

• A substantial proportion (64%) of participants were on background PAH-specific therapy, which complicates the isolation of macitentan's specific efficacy, though it mirrors real-world clinical practice.

• The primary endpoint was a composite that relies on clinical worsening definitions, which can be subject to adjudication variability.

• Long-term outcomes beyond the study follow-up period remain necessary to assess the durability of the clinical benefit.

Clinical Significance

The SERAPHIN trial established macitentan as a significant therapeutic option for PAH by using a rigorous, event-driven, morbidity-mortality endpoint rather than relying solely on exercise capacity (6-minute walk distance). It provided evidence that dual endothelin receptor antagonism can delay disease progression and reduce hospitalizations, supporting its use in both treatment-naive patients and those on background therapy.

Historical Context

Prior to SERAPHIN, most PAH drug approvals were based on short-term trials (12-16 weeks) using improvements in the 6-minute walk distance as a surrogate endpoint. The SERAPHIN trial marked a major shift in the field by utilizing a long-term, event-driven primary outcome, providing more clinically relevant data on morbidity reduction and disease progression in a chronic, life-limiting condition.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the dual blockade of endothelin receptors (ETA and ETB) by macitentan counteract the pathophysiology of pulmonary arterial hypertension (PAH)?

Key Response

In PAH, endothelin-1 is overexpressed, leading to vasoconstriction and vascular remodeling. Macitentan targets ET-A receptors (which mediate vasoconstriction and proliferation) and ET-B receptors (which mediate similar effects in diseased vessels), whereas selective antagonists only target ET-A. Understanding this mechanism explains why ERAs are a cornerstone of preventing right heart failure in these patients.

Resident

In clinical practice, how does the safety profile and monitoring requirements of macitentan, based on the SERAPHIN data, differ from the first-generation ERA bosentan?

Key Response

Unlike bosentan, which is associated with a risk of hepatotoxicity requiring monthly liver function test (LFT) monitoring, the SERAPHIN trial demonstrated that macitentan did not cause a significant increase in aminotransferase levels compared to placebo. This reduced monitoring burden significantly influences long-term patient compliance and management of PAH in the outpatient setting.

Fellow

The SERAPHIN trial was the first to use a 'time-to-event' composite endpoint rather than a change in 6-minute walk distance (6MWD). How does this shift in trial design change our interpretation of long-term treatment efficacy in PAH?

Key Response

Previous PAH trials focused on 6MWD, which is a surrogate for functional capacity but often fails to correlate with long-term survival. By utilizing a composite endpoint of morbidity (worsening of PAH, hospitalization) and mortality, SERAPHIN provided more robust evidence that macitentan impacts the natural history and disease progression of PAH, establishing a higher standard for subsequent phase III trials.

Attending

Considering that 64% of patients in SERAPHIN were already on background therapy (predominantly PDE5 inhibitors), how does this evidence support the shift toward upfront or early sequential combination therapy in modern PAH management?

Key Response

Subgroup analysis in SERAPHIN showed that macitentan was effective regardless of whether patients were treatment-naive or receiving background therapy. This validates the 'sequential combination therapy' strategy to reduce morbidity, suggesting that we should not wait for clinical deterioration before adding a second class of vasodilator to a patient's regimen.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critically evaluate the statistical impact of including 'initiation of other PAH treatments' within the composite morbidity endpoint: to what extent might this lead to an overestimation of the drug's biological effect due to investigator bias?

Key Response

In open-label clinical practice, the decision to start a new therapy is subjective. If investigators were not perfectly blinded, or if clinical deterioration was perceived prematurely, the 'morbidity' event could be triggered by clinician behavior rather than physiological failure. A PhD researcher would look for sensitivity analyses excluding these 'soft' components to confirm that the hazard ratio remains significant based on 'hard' outcomes like hospitalization or death.

Journal Editor

Given the global nature of the SERAPHIN trial, how do the varying standards of 'usual care' across different geographic regions impact the external validity and generalizability of the findings to high-resource healthcare systems?

Key Response

A journal editor would flag potential heterogeneity in results across regions. If the benefit was disproportionately driven by regions with lower access to rescue therapies, the 45% risk reduction might be inflated compared to what would be seen in centers where patients have immediate access to parenteral prostacyclins upon worsening, requiring a careful assessment of the interaction between region and treatment effect.

Guideline Committee

Based on the SERAPHIN results, how should macitentan be positioned in the ESC/ERS treatment algorithm compared to older agents with Class I-A recommendations based on 6MWD data?

Key Response

While older agents may have 'Level A' evidence from multiple small trials, macitentan’s 'Level B' evidence is derived from a trial specifically powered for long-term clinical events. The committee must decide if event-driven data (SERAPHIN) should carry more weight than meta-analyses of short-term surrogate trials, likely resulting in a Class I, Level B recommendation for macitentan as a preferred ERA to delay clinical worsening.

Clinical Landscape

Noteworthy Related Trials

2002

BREATHE-1 Trial

n = 213 · NEJM

Tested

Bosentan (dual endothelin receptor antagonist)

Population

Patients with WHO functional class III or IV pulmonary arterial hypertension

Comparator

Placebo

Endpoint

Change in 6-minute walk distance

Key result: Bosentan therapy improved exercise capacity and delayed clinical worsening compared to placebo.

2007

ARIES Trial

n = 200 · JACC

Tested

Ambrisentan (selective endothelin-A receptor antagonist)

Population

Patients with pulmonary arterial hypertension

Comparator

Placebo

Endpoint

Change in 6-minute walk distance

Key result: Ambrisentan significantly improved exercise capacity and increased the time to clinical worsening.

2015

GRIPHON Trial

n = 1156 · NEJM

Tested

Selexipag (oral selective IP prostacyclin receptor agonist)

Population

Patients with symptomatic pulmonary arterial hypertension

Comparator

Placebo

Endpoint

Morbidity and mortality composite endpoint

Key result: Selexipag significantly reduced the risk of morbidity and mortality events in patients with PAH.

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