Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients with Pulmonary Arterial Hypertension: Insights from the Phase III GRIPHON Study

Kelly M. Chin, Lewis J. Rubin, Richard Channick, Lilla Di Scala, Sean Gaine, Nazzareno Galiè, Hossein Ardeschir Ghofrani, Marius M. Hoeper, Irene M. Lang, Vallerie V. McLaughlin, Ralph Preiss, Gérald Simonneau, Olivier Sitbon, Victor F. Tapson

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2440-2450
Number of pages11
JournalCirculation
Volume139
Issue number21
DOIs
StatePublished - May 21 2019

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Keywords

  • brain natriuretic peptide
  • hypertension, pulmonary
  • prostacyclin receptor
  • risk assessment

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Chin, K. M., Rubin, L. J., Channick, R., Di Scala, L., Gaine, S., Galiè, N., Ghofrani, H. A., Hoeper, M. M., Lang, I. M., McLaughlin, V. V., Preiss, R., Simonneau, G., Sitbon, O., & Tapson, V. F. (2019). Association of N-Terminal Pro Brain Natriuretic Peptide and Long-Term Outcome in Patients with Pulmonary Arterial Hypertension: Insights from the Phase III GRIPHON Study. Circulation, 139(21), 2440-2450. https://doi.org/10.1161/CIRCULATIONAHA.118.039360