To treat or not to treat: Pulmonary hypertension due to chronic lung disease

Background: Pulmonary hypertension (PH) represents a frequent and prognostically important complication of chronic lung diseases, classified as group 3 PH. Highly prevalent in advanced chronic obstructive pulmonary disease (COPD) and end-stage idiopathic pulmonary fibrosis (IPF), group 3 PH independently predicts mortality, with studies that demonstrate worse long-term survival compared with other PH groups. The pathophysiology involves chronic alveolar hypoxia driving vascular remodeling through medial hypertrophy, intimal fibrosis, and smooth muscle proliferation, with disease-specific mechanisms, which include hypoxic vasoconstriction in COPD and fibrotic vascular ablation in interstitial lung disease (ILD). Despite the appeal of repurposing proven pulmonary vasodilators, clinical trials have yielded predominantly disappointing results with notable safety concerns. Methods: We conducted an expert narrative review of the most important clinical trials in group 3 PH. Results: Phosphodiesterase-5 inhibitors showed mixed outcomes, with sildenafil demonstrating modest benefits in select patients with COPD and with severe PH but failing to show efficacy in IPF trials. Endothelin receptor antagonists proved harmful, with ambrisentan increasing disease progression and mortality in IPF, resulting in contraindication. Riociguat similarly failed in ILD-PH, demonstrating increased mortality without efficacy. The notable exception is inhaled treprostinil, which became the first U.S. Food and Drug Administration approved therapy for ILD-PH after a landmark randomized controlled trial's demonstration of improved 6-minute walk distance, reduced clinical worsening, and preserved lung function without compromising gas exchange. Conversely, a subsequent randomized controlled trial revealed increased mortality with inhaled treprostinil in COPD-PH, particularly among patients with severe gas exchange impairment. Conclusion: These contrasting outcomes underscore the phenotypic heterogeneity within group 3 PH and emphasize that therapeutic approaches cannot be uniformly applied across different underlying lung diseases. Current management remains focused on optimizing underlying lung disease and providing supplemental oxygen, with pulmonary vasodilators reserved for carefully selected patients at expert centers. Future research must prioritize patient phenotyping to identify responder profiles and explore novel therapeutic targets beyond traditional vasodilator pathways.