Hypotensive Events Associated With PDE-5 Inhibitors in Pulmonary Arterial Hypertension: Assessment of the USFDA Adverse Event Reporting System Using Disproportionality and Interaction Analysis.

Abstract

Background: Phosphodiesterase-5 inhibitors (PDE-5is) are fundamental in pulmonary arterial hypertension (PAH) treatment, often used in combination with other therapeutic agents. However, hypotension signals associated with these combinations remain inadequately characterized. We analyzed the United States Food and Drug Administration Adverse Event Reporting System (FAERS) to evaluate disproportionate signals of hypotension associated with PDE-5is alone and in combination therapy.

Methods: We conducted a pharmacovigilance analysis of FAERS data from 2004 to 2024, employing both frequentist (reporting odds ratio, proportional reporting ratio) and Bayesian (information component, empirical Bayes geometric mean) approaches. Interaction signal scores (INTSS) were calculated to assess potential drug interactions between PDE-5is and other PAH therapies. Clinical outcomes were evaluated for both monotherapy and combination regimens.

Results: Among 29 163 222 reports analyzed, 704 cases of PDE-5i-associated hypotension were identified (533 monotherapy, 171 combination therapy). While PDE-5i monotherapy showed no significant hypotension signals, combinations with endothelin antagonists (particularly bosentan) and prostacyclin analogs (notably epoprostenol) generated strong safety signals. Significant INTSS were detected for sildenafil and tadalafil with endothelin antagonists. Paradoxically, despite fewer hypotension reports, PDE-5i monotherapy was associated with higher rates of death and life-threatening events compared to combination therapy (P = .02).

Conclusion: This analysis reveals significant hypotension signals with specific PDE-5i combinations in PAH treatment, particularly with endothelin antagonists and prostacyclin analogs. While combination therapy showed a higher frequency of hypotensive events, these episodes appeared more manageable than those occurring with monotherapy. These findings emphasize the need for careful monitoring and individualized risk assessment in PAH patients receiving PDE-5i-based therapy.