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.