The New England Journal of Medicine DECEMBER 24, 2015

Selexipag for the Treatment of Pulmonary Arterial Hypertension

Nazzareno Galiè, M.D., et al.

Bottom Line

The GRIPHON trial demonstrated that the oral, selective prostacyclin-receptor agonist selexipag significantly reduced the risk of a primary composite endpoint of morbidity and mortality in patients with pulmonary arterial hypertension.

Key Findings

1. Selexipag significantly reduced the risk of the primary composite endpoint (death or a complication related to PAH) by 40% (hazard ratio 0.60; 99% CI, 0.46 to 0.78; P<0.001).

2. Primary endpoint events occurred in 27.0% of the selexipag group compared to 41.6% in the placebo group.

3. The benefit of selexipag was observed regardless of whether patients were receiving background PAH therapy or were treatment-naive at baseline.

4. Common adverse events associated with selexipag were consistent with prostacyclin-pathway therapy, including headache, diarrhea, and nausea, which were more frequent in the intervention group.

Study Design

Design

RCT

Double-Blind

Sample

1,156

Patients

Duration

Not specified

Median

Setting

Multicenter, international

Population Patients aged 18 to 75 with symptomatic pulmonary arterial hypertension (WHO functional class II or III) who were either treatment-naive or receiving background therapy with an endothelin receptor antagonist, a phosphodiesterase type 5 inhibitor, or both.

Intervention Oral selexipag initiated at 200 µg twice daily, with individualized dose titration up to a maximum of 1600 µg twice daily based on tolerability.

Comparator Matching oral placebo twice daily, titrated according to the same schedule as the intervention arm.

Outcome Time from randomization to the first morbidity or mortality event, defined as death, atrial septostomy, lung transplantation, initiation of parenteral prostanoid therapy, or worsening of pulmonary arterial hypertension.

Study Limitations

• The study experienced a relatively high rate of treatment discontinuation (approximately 19%) in the selexipag group, primarily due to adverse events.

• The study population was primarily composed of patients with WHO functional class II and III, which may limit generalizability to more severe classes.

• While the trial reached its primary endpoint, it was not powered to detect a significant difference in mortality alone.

Clinical Significance

The GRIPHON trial established selexipag as an effective oral therapeutic option for patients with PAH, providing a non-parenteral alternative for targeting the prostacyclin pathway and reducing morbidity/mortality risk, thus improving the management landscape for clinicians treating this condition.

Historical Context

Prior to the GRIPHON trial, prostacyclin-pathway treatments (e.g., epoprostenol, treprostinil) were primarily administered via parenteral routes, which are complex and carry significant risks. Selexipag, as an oral selective IP receptor agonist, offered a novel and more convenient mechanism to target this pathway, changing the standard of care for patients with PAH.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of selexipag differ from that of epoprostenol, and how does this affect its route of administration?

Key Response

Selexipag is a selective prostacyclin (IP) receptor agonist, whereas epoprostenol is a non-selective prostacyclin analog that acts on various prostanoid receptors. Because selexipag and its active metabolite are chemically stable and have longer half-lives, they can be administered orally twice daily, unlike epoprostenol which requires continuous intravenous infusion due to its extremely short half-life (minutes).

Resident

In a patient already treated with an endothelin receptor antagonist (ERA) and a phosphodiesterase-5 (PDE5) inhibitor, what specific benefit does adding selexipag provide according to the GRIPHON trial results?

Key Response

The GRIPHON trial demonstrated that selexipag reduced the risk of the composite primary endpoint of morbidity and mortality by 40%. Crucially, this benefit was consistent across patients who were already receiving background dual therapy, showing that selexipag is effective as part of a triple-therapy regimen to prevent disease progression and PAH-related hospitalizations.

Fellow

The GRIPHON trial showed a significant reduction in the primary composite endpoint but failed to show a significant difference in all-cause mortality. How should this discrepancy influence the clinical decision to start selexipag in a WHO Functional Class III patient?

Key Response

Fellows must recognize that the trial was powered for a composite 'morbidity/mortality' endpoint, which was primarily driven by reductions in disease progression and hospitalization rather than survival. In FC III patients, selexipag should be viewed as a tool to maintain stability and delay clinical worsening, but it may not replace the need for parenteral prostacyclins if the goal is a mortality benefit or rapid hemodynamical rescue.

Attending

Given the titration-related side effects observed in GRIPHON (headache, diarrhea, jaw pain), what is the most effective clinical strategy for achieving the individualized maintenance dose while ensuring long-term patient adherence?

Key Response

Attending-level management involves 'start low, go slow' titration and proactive side-effect management. Because the individual maintenance dose varies (ranging from 200 to 1600 mcg), the focus is on the patient's tolerability rather than reaching a fixed target. Education on transient versus persistent side effects and the use of ancillary medications (e.g., NSAIDs for headache) is vital for long-term compliance.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Evaluate the use of a time-to-event composite primary endpoint in the GRIPHON trial. What are the potential statistical biases introduced when 'disease progression' is defined by a 15% decrease in 6-minute walk distance combined with a change in Functional Class?

Key Response

Using a composite endpoint where components have different clinical weights can be problematic. A reduction in 6MWD is a subjective/soft endpoint compared to death. If the treatment effect is primarily driven by the softer components, the 'statistical' success may overstate the 'clinical' impact. Methodologists would look for a sensitivity analysis or a win-ratio approach to ensure the effect on death is not masked or contradicted by the effect on morbidity.

Journal Editor

Considering the study population in GRIPHON was approximately 46% WHO Functional Class II, to what extent does this 'healthier' cohort limit the trial's applicability to the most vulnerable PAH patients, and did the inclusion of these patients artificially inflate the safety profile?

Key Response

Editors look for threats to external validity. Including a high proportion of FC II patients may lead to a more favorable safety profile and fewer discontinuations due to adverse events than would be seen in a purely FC III/IV population. A tough reviewer would ask for subgroup analyses specifically focusing on the higher-risk patients to ensure the hazard ratio remains robust across severity strata.

Guideline Committee

How does the GRIPHON trial evidence impact the ESC/ERS recommendations for 'sequential triple therapy' compared to the previous standards of care that prioritized parenteral agents?

Key Response

Based on GRIPHON, the 2022 ESC/ERS guidelines gave selexipag a Class IB recommendation for sequential combination therapy in patients with low or intermediate risk of mortality. This moved selexipag into a prominent position for oral triple therapy, though parenteral prostacyclins remain the Class IA/B recommendation for high-risk patients due to their more potent hemodynamic effects and established survival data.

Clinical Landscape

Noteworthy Related Trials

2002

BREATHE-1 Trial

n = 213 · NEJM

Tested

Bosentan

Population

Patients with WHO class III or IV pulmonary arterial hypertension

Comparator

Placebo

Endpoint

Change from baseline in 6-minute walk distance

Key result: Bosentan significantly improved exercise capacity and delayed the time to clinical worsening in patients with PAH.

2013

SERAPHIN Trial

n = 742 · NEJM

Tested

Macitentan

Population

Symptomatic pulmonary arterial hypertension patients

Comparator

Placebo

Endpoint

Composite of death, atrial septostomy, lung transplantation, initiation of prostanoids, or worsening of PAH

Key result: Macitentan significantly reduced the risk of morbidity and mortality among patients with pulmonary arterial hypertension.

2015

AMBITION Trial

n = 500 · NEJM

Tested

Ambrisentan plus Tadalafil

Population

Treatment-naive pulmonary arterial hypertension patients

Comparator

Ambrisentan monotherapy or Tadalafil monotherapy

Endpoint

Time to first clinical failure event

Key result: Initial combination therapy with ambrisentan and tadalafil significantly reduced the risk of clinical failure compared with monotherapy.

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