A Breath of Life Beyond Bronchodilation: Early Data on Hemodynamic and Functional Outcomes With Ensifentrine Nebulization in Severe COPD-associated Pulmonary Hypertension

Introduction Pulmonary hypertension (PH) is a frequent and serious complication of advanced chronic obstructive pulmonary disease (COPD) and is associated with a poor prognosis and limited treatment options. Current management focuses on optimizing COPD care, while the role of pulmonary vasodilators remains controversial. Ensifentrine, a dual phosphodiesterase (PDE) 3/4 inhibitor with bronchodilatory and anti-inflammatory properties, may offer a therapeutic benefit in COPD-associated PH. This study aims to retrospectively evaluate the effects of six months of nebulized ensifentrine on pulmonary hemodynamics and functional outcomes in patients with severe COPD and associated pre-capillary PH. Methods We conducted a single-center, retrospective chart review of patients with GOLD stage III and IV COPD and confirmed pre-capillary PH (mean pulmonary artery pressure [mPAP] ≥20 mmHg, pulmonary vascular resistance [PVR] >2 Wood units, pulmonary capillary wedge pressure ≤15 mmHg). Five patients treated with nebulized ensifentrine (3 mg twice daily) between September 2024 and May 2025 were included. Hemodynamics via right heart catheterization (RHC) and 6-minute walk distance (6MWD) were measured at baseline and at 6 months. Results The cohort (mean age 76 years, 60% male, mean FEV 1 33.4% predicted) demonstrated severe emphysema and PH (baseline mPAP 53.2 mmHg, PVR 9.5 WU, cardiac index 2.5 L/min/m 2 ). After 6 months, mean changes were as follows: •mPAP: decrease by 1.6 mmHg •Cardiac index: increase by 0.1 L/min/m 2 •PVR: decrease by 1.0 WU6MWD: improved by 31 m •mMRC dyspnea score improved from 3.6 to 3.2 •CAT score from 23 to 21.6 •DLCO increased modestly (29%→31.2% predicted). •No adverse events, exacerbations, or hospitalizations were observed during this period. •The combination of ensifentrine with roflumilast was well tolerated. Discussion Pulmonary hypertension in COPD is associated with worse outcomes, yet treatment options remain limited and uncertain. In this small retrospective case series of five patients with very severe COPD and confirmed pre-capillary PH, the addition of ensifentrine to optimized therapy was associated with modest but potentially meaningful improvements in symptoms, exercise capacity (6MWD), and select hemodynamic parameters, without worsening oxygenation. Its dual PDE3/PDE4 inhibition and inhaled delivery provide a plausible mechanism for bronchodilation, anti-inflammatory effects, and selective pulmonary vasodilation while minimizing ventilation–perfusion mismatch. However, the findings are highly preliminary given the very small sample size, lack of a control group, retrospective design, and significant selection bias, limiting generalizability and causal inference. Overall, the results are hypothesis-generating and suggest that ensifentrine may have therapeutic potential in COPD-associated PH, but larger, prospective, randomized trials are needed to confirm efficacy, safety, and its role in treatment algorithms. Conclusions In this retrospective study, ensifentrine was safe and was associated with modest improvements in pulmonary hemodynamics and functional status in patients with severe COPD with pre-capillary PH. These preliminary findings warrant confirmation in larger, prospective, controlled trials.