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Key Clinical Summary: Rethink Pulmonary Arterial Hypertension - Optimize Escalation and Combination Therapy

This is a micro-learning module summary of a presentation by Dr. Sudarshan Rajagopal, which you can find here. Before participating, please read our CME and disclosure information which can be found here.

This program is supported by an independent educational grant from MSD. This online education program is designed solely for healthcare professionals in the USA. The content is not available for HCPs in any other country.

Myth 2: Monotherapy Is Usually Enough

Introduction

This summary examines contemporary evidence demonstrating the limitations of monotherapy in pulmonary arterial hypertension (PAH), outlining the evolution of treatment strategies from single‑agent therapy toward routine upfront combination regimens. It reviews current risk‑based treatment algorithms and key clinical trial data supporting dual, triple, and emerging quadruple therapy approaches.

Risk‑Based Treatment Framework in PAH

  • Modern PAH management is anchored in structured, repeated risk assessment
  • The World Symposium on Pulmonary Hypertension treatment algorithm emphasizes:
    • Initial evaluation followed by scheduled reassessment
    • Escalation of therapy for patients who fail to achieve or maintain low‑risk status
  • Treatment intensity is matched to the risk category, with combination therapy recommended for most patients at diagnosis
  • The traditional stepwise escalation model, starting with monotherapy and adding agents only after clinical decline, is no longer considered adequate for optimal outcomes

Limitations of Monotherapy

  • Historical reliance on monotherapy reflected earlier eras of limited therapeutic options and less standardized risk stratification
  • Evidence from multiple clinical trials demonstrates that monotherapy rarely achieves sustained low‑risk status
  • Patients treated with a single agent often experience:
    • Persistent symptoms
    • Incomplete hemodynamic improvement
    • High rates of clinical worsening
  • Current guidelines and consensus statements now position monotherapy as appropriate only for a narrow subset of low‑risk patients or those with contraindications to combination therapy

Evidence Supporting Dual Therapy

SERAPHIN: Macitentan Added to Background Therapy

  • The SERAPHIN trial evaluated macitentan in patients with PAH, 64% of whom were already receiving background therapy
  • Baseline background therapy included 62% of patients on phosphodiesterase‑5 inhibitors (PDE5i) and 5% on prostanoids
  • Macitentan significantly reduced morbidity and mortality events* compared with placebo (HR 0.55; 97.5% CI 0.39–0.76; p<0.001) for macitentan 10 mg
  • Benefits were observed regardless of whether patients were treatment‑naïve or receiving background therapy
  • The trial provided early evidence that adding an endothelin receptor antagonist (ERA) to existing therapy improves long‑term outcomes

*Worsening of PAH, initiation of treatment with intravenous or subcutaneous prostanoids, lung transplantation or atrial septostomy; death from any cause

GRIPHON: Selexipag Added to ERA and/or PDE5i Therapy

  • The GRIPHON trial evaluated the oral prostacyclin receptor agonist selexipag in a population where 80% were already on background therapy
  • Background regimens included 47% of patients on either an ERA or PDE5i and 33% on ERA + PDE5i dual therapy
  • Selexipag reduced the risk of morbidity and mortality events* by 40% (HR 0.60; 99% CI 0.46–0.78; p<0.001)
  • Benefits were consistent across subgroups, including those already receiving dual therapy.
  • These results reinforced the principle that sequential addition of prostacyclin‑pathway agents improves outcomes even in patients already on combination therapy

*Death or PAH complication (disease progression or worsening of PAH resulting in hospitalization, initiation of parenteral prostanoid therapy or long-term oxygen therapy, or need for lung transplantation or balloon atrial septostomy)

Evidence Supporting Triple and Quadruple Therapy

HYPERION: Sotatercept in Early PAH

  • The HYPERION trial evaluated sotatercept within the first year after PAH diagnosis
  • Most participants were receiving dual oral therapy; a smaller proportion were on triple therapy
  • Sotatercept markedly reduced the risk of clinical worsening events* (HR 0.24; 95% CI 0.14–0.41; p<0.001)
  • Benefits were observed despite patients already receiving optimized background therapy
  • These results align with findings from STELLAR, which enrolled predominantly intermediate‑risk patients on triple therapy, and ZENITH, which enrolled high‑risk patients, largely on triple therapy
  • Across studies, sotatercept consistently improved functional, hemodynamic, and clinical outcomes, supporting its role as an add‑on therapy in patients not achieving low‑risk status

*Death from any cause, unplanned hospitalization lasting ≥24 hours for worsening of PAH, atrial septostomy, lung transplantation, or deterioration in performance in exercise testing due to PAH

Clinical Implications: Moving Beyond Stepwise Escalation

  • Cumulative evidence from SERAPHIN, GRIPHON, HYPERION, STELLAR, and ZENITH demonstrates that:
    • Monotherapy is insufficient for most patients
    • Dual therapy is now considered the minimum standard for newly diagnosed PAH
    • Triple therapy is appropriate for intermediate‑ and high‑risk patients
    • Quadruple therapy, including the addition of sotatercept, is emerging as a strategy for patients who remain above low‑risk thresholds despite optimized therapy
  • Risk‑based treatment intensification is now central to PAH management, with therapy escalation guided by functional class, 6‑minute walk distance, biomarkers, hemodynamics, and clinical events

Conclusions
The contemporary management of PAH has shifted decisively away from monotherapy, driven by robust clinical trial evidence demonstrating the superiority of combination approaches. Dual therapy is now standard at diagnosis for most patients, while triple and quadruple regimens are increasingly used to achieve and maintain low‑risk status. Agents targeting multiple complementary pathways provide additive benefits when used together. Risk‑based treatment algorithms underscore the need for early escalation rather than stepwise intensification. As the therapeutic landscape continues to evolve, combination therapy remains the cornerstone of improving long‑term outcomes in PAH.

Content is accurate as of the date of release on 13 February 2026.