Association of NT-proBNP and Long-Term Outcome in Patients with Pulmonary Arterial Hypertension: Insights from the Phase III GRIPHON Study

Science and Research

BACKGROUND: N-terminal pro brain natriuretic peptide (NT-proBNP) levels are included in the multiparametric risk assessment approach for pulmonary arterial hypertension (PAH) outlined in PAH guidelines. However, data supporting use of NT-proBNP risk thresholds in assessing prognosis in PAH are limited. The GRIPHON trial 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 randomized 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 two independent sets of thresholds: 1) baseline tertiles: <271 ng/L; 271-1165 ng/L; >1165 ng/L; 2) 2015 ESC/ERS guideline cut-offs: <300 ng/L; 300-1400 ng/L; >1400 ng/L. Hazard ratios (selexipag vs placebo; HRs) with 95% confidence intervals (CIs) were calculated for the primary endpoint (composite morbidity/mortality events) by NT-proBNP category at baseline using Cox proportional-hazard 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, compared with patients with a high NT-proBNP level. Selexipag reduced the risk of morbidity/mortality events across all three 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 two 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 ESC/ERS guidelines for the management of PAH patients. CLINICAL TRIAL REGISTRATION: URL: