Pulmonary Arterial Hypertension-approved drugs in Pulmonary Hypertension associated with COPD: A systematic literature review

Abstract

Introduction: Pulmonary hypertension (PH) is commonly associated with chronic obstructive pulmonary disease (COPD), with an estimated prevalence of 39%. PH reduces functional capacity and exercise tolerance, and increases the risk of COPD exacerbations and hospitalizations. PH associated with COPD (PH-COPD) typically manifests with moderate severity, progressing gradually in tandem with the level of bronchial obstruction. However, a specific subgroup with severe PH displays disproportionately high pulmonary vascular resistance, reduced diffusion capacity, and a severe prognosis.

Methods: This article is a systematic literature review of clinical trials including randomized controlled trials (RCTs), non-RCTs, cohort studies and registry data regarding PAH-approved drugs, in the context of PH-COPD, from January 2003 to January 2025.

Results: There have been three positive and three negative RCTs with phosphodiesterase-5 inhibitors, as well as one positive and one negative RCT with endothelin receptor antagonists. These RCTs suffered from limitations especially in severe PH cases. Additional data came from 16 studies, including non-RCTs, cohort studies and registry data, and the results were conflicting. The most robust study, a large phase 3 RCT using inhaled treprostinil, was terminated early due to an unfavorable benefit-risk ratio.

Conclusion: The evidence does not support PAH-approved drugs for mild-to-moderate PH-COPD, though potential benefits may exist for the severe PH subgroup. Large, multicenter RCTs are necessary to provide robust medical evidence and phase 2 and phase 3 clinical trials are ongoing. In the interim, suspected or confirmed severe PH-COPD should prompt referral to PH centers for personalized care and potential clinical trial participation.

Keywords: Chronic obstructive pulmonary disease; Pulmonary arterial hypertension-approved drugs; Pulmonary hypertension.