Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients With Pulmonary Arterial Hypertension

Circulation. 2019 May 21;139(21):2440-2450. doi: 10.1161/CIRCULATIONAHA.118.039360.


Background: NT-proBNP (N-terminal pro brain natriuretic peptide) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidelines. However, data supporting the use of NT-proBNP risk thresholds in assessing prognosis in PAH are limited. The GRIPHON trial (Prostacyclin [PGI2] Receptor Agonist In Pulmonary Arterial Hypertension) provides an opportunity to assess the prognostic value of NT-proBNP thresholds in a controlled clinical trial and to evaluate the response to selexipag according to these thresholds.

Methods: The event-driven GRIPHON trial randomly assigned patients to selexipag or placebo. NT-proBNP was measured at regular intervals in GRIPHON. Here, patients were categorized post hoc into low, medium, and high NT-proBNP subgroups according to 2 independent sets of thresholds: (1) baseline tertiles: <271 ng/L; 271 to 1165 ng/L; >1165 ng/L; and (2) 2015 European Society of Cardiology/European Respiratory Society guidelines cutoffs: <300 ng/L; 300 to 1400 ng/L; >1400 ng/L. Hazard ratios (selexipag versus placebo) with 95% CIs were calculated for the primary end point (composite morbidity/mortality events) by NT-proBNP category at baseline using Cox proportional-hazards models, and at any time during the exposure period using a time-dependent Cox model.

Results: With both thresholds, baseline and follow-up NT-proBNP categories were highly prognostic for future morbidity/mortality events during the study ( P<0.0001). In the time-dependent analysis, the risk of experiencing a morbidity/mortality event was 92% and 83% lower in selexipag-treated patients with a low and medium NT-proBNP level, and 90% and 56% lower in placebo-treated patients with a low and medium NT-proBNP level, in comparison with patients with a high NT-proBNP level. Selexipag reduced the risk of morbidity/mortality events across all 3 NT-proBNP categories in both the baseline and time-dependent analyses, with a more pronounced treatment benefit of selexipag seen in the medium and low NT-proBNP subgroups (interaction P values 0.20 and 0.007 in the baseline and time-dependent analyses).

Conclusions: These analyses further establish the prognostic relevance of NT-proBNP levels in PAH and provide first evidence for the association of NT-proBNP level and treatment response. Using 2 similar sets of thresholds, these analyses support the relevance of the low, medium, and high NT-proBNP categories as part of the multiparametric risk assessment approach outlined in the European Society of Cardiology/European Respiratory Society guidelines for the management of PAH patients.

Clinical trial registration: URL: . Unique identifier: NCT01106014.

Keywords: brain natriuretic peptide; hypertension, pulmonary; prostacyclin receptor; risk assessment.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / therapeutic use
  • Adolescent
  • Adult
  • Aged
  • Antihypertensive Agents / therapeutic use
  • Arterial Pressure* / drug effects
  • Biomarkers / blood
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / blood*
  • Peptide Fragments / blood*
  • Pulmonary Arterial Hypertension / blood*
  • Pulmonary Arterial Hypertension / drug therapy
  • Pulmonary Arterial Hypertension / mortality
  • Pulmonary Arterial Hypertension / physiopathology
  • Pulmonary Artery / drug effects
  • Pulmonary Artery / physiopathology*
  • Pyrazines / therapeutic use
  • Risk Assessment
  • Risk Factors
  • Time Factors
  • Treatment Outcome
  • Young Adult


  • Acetamides
  • Antihypertensive Agents
  • Biomarkers
  • Peptide Fragments
  • Pyrazines
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain
  • selexipag

Associated data