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

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.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01106014.

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

Figure 1.

Shift table for change in NT-proBNP (N-terminal pro brain natriuretic peptide) category from baseline to week 26. Values are shown as n (%). Low, medium, and high NT-proBNP cutoffs were determined according to baseline NT-proBNP tertiles (low: <271 ng/L; medium: 271–1165 ng/L; high: >1165 ng/L). Analyses were performed only in patients who were still in the double-blind treatment at week 26 and who had an NT-proBNP value at baseline and week 26; 289 patients randomly assigned at baseline were excluded from these analyses for the following reasons (categories are not mutually exclusive): primary end point event before week 26 (n=147), premature discontinuation of double-blind treatment before week 26 (n=121), missing NT-proBNP value at baseline (n=14) or at week 26 (n=239). BL indicates baseline.

Figure 2.

Time from randomization to first morbidity or mortality event in subgroups defined by NT-proBNP (N-terminal pro brain natriuretic peptide) level at baseline. Low, medium, and high NT-proBNP cutoffs were determined according to baseline NT-proBNP tertiles (low: <271 ng/L; medium: 271–1165 ng/L; high: >1165 ng/L).

Figure 3.

Time from week 26 to first morbidity or mortality event based on change in NT-proBNP (N-terminal pro brain natriuretic peptide) category from baseline to week 26 for placebo and selexipag patients. Data shown for (A) patients receiving placebo and (B) patients receiving selexipag. Low, medium, and high NT-proBNP cutoffs determined according to baseline NT-proBNP tertiles (low: <271 ng/L; medium: 271–1165 ng/L; high: >1165 ng/L). Subgroups are defined as: stable low (low NT-proBNP at baseline and at week 26), stable medium (medium NT-proBNP at baseline and at week 26), stable high (high NT-proBNP at baseline and at week 26), improved (high at baseline and medium or low at week 26, or medium at baseline and low at week 26), and deteriorated (low at baseline and medium or high at week 26, or medium at baseline and high at week 26).

Figure 4.

Treatment effect of selexipag on time from randomization to first morbidity or mortality event. A, Treatment effect in subgroups defined by NT-proBNP (N-terminal pro brain natriuretic peptide) level at baseline. B, Treatment effect by time-dependent NT-proBNP category. Low, medium, and high NT-proBNP cutoffs were determined according to baseline NT-proBNP tertiles (low: <271 ng/L; medium: 271–1165 ng/L; high: >1165 ng/L). HR indicates hazard ratio; and N/A, not available.

Figure 5.

Subpopulation treatment effect pattern plot showing the treatment effect of selexipag vs placebo on morbidity/mortality (hazard ratio plus 95% CIs and 95% confidence bands) by NT-proBNP (N-terminal pro brain natriuretic peptide) level at baseline. The black line indicates the hazard ratio of each subpopulation, the dark blue dashed line indicates the 95% CI for each individual subpopulation. The light blue dashed line shows the 95% confidence bands, which define the confidence interval of the best-fit line and indicate with 95% certainty the bounds within which the true curve will fall. Vertical lines indicate the 300 ng/L and 1400 ng/L NT-proBNP thresholds. HR indicates hazard ratio.