ATS 2025: The Minimal Important Difference in NT-proBNP in Various Forms of Pulmonary Hypertension

Introduction:

N-terminal pro-brain natriuretic peptide (NT-proBNP) is used to assess disease severity in pulmonary hypertension including pulmonary arterial hypertension (PAH) and pulmonary hypertension associated with interstitial lung disease (PH-ILD). While improvements in NT-proBNP in PAH patients have been linked to favorable long-term outcomes, the minimal important difference (MID) for NT-proBNP change has not been previously defined.

Methods:

Data from two registration trials were analyzed to determine the MID of NT-proBNP change: FREEDOM-EV (oral treprostinil v/s placebo) in PAH and INCREASE (inhaled treprostinil v/s placebo) in PH-ILD. Distribution-based methods were applied to determine the percent change in NT-proBNP  for the FREEDOM-EV trial measured at 12 weeks and for the INCREASE trial measured at 16 weeks. Association between achieving the MID and occurrence of clinical worsening event in FREEDOM-EV trial were assessed using Kaplan-Meier analysis. Least-squares mean was used to compare difference in 6-minute walk distance (6MWD) improvement between those achieving and not achieving MID in INCREASE trial. Placebo and active treatment groups from both the trials were combined for all analyses.

Results:

1. In FREEDOM-EV, complete data was available for 638 PAH patients (average age 45 years, 79% female, idiopathic PAH 63%, connective tissue disease (CTD) PAH 26%) with the median MID for NT-proBNP change being -36%. PAH patients not achieving the MID at 12 weeks were 61% more likely to experience a clinical worsening event during long term follow up. (HR 1.61, 95% CI 1.14–2.33, p = 0.008).
2. In INCREASE, complete data was available for 250 PH-ILD patients (average age 66.5 years, 49% female, idiopathic pulmonary fibrosis 46%, CTD-ILD 25%) with the median MID for NT-pro BNP change being -38%. PH-ILD patients achieving the MID at 16 weeks showed a 35.6 meter improvement in 6MWD compared to those who did not (12.5, 58.9m, p = 0.003).

Conclusion:

The MID for NT-proBNP change was estimated at -36% in PAH and -38% in PH-ILD. Failure to achieve the MID was strongly associated with clinically important outcomes, indicating that assessing NT-proBNP change over 12–16 weeks may aid in prognosis and treatment escalation decisions for both PAH and PH-ILD.

Am J Respir Crit Care Med 2025; 211: A3280

American Thoracic Society 2025 International Conference, May 18-21, San Francisco