We read with great interest the meta-analysis by Xiao et al. [1] on the efficacy of oral treprostinil in pulmonary arterial hypertension (PAH), which highlights significant benefits in delaying clinical worsening and improving exercise capacity, though with notable adverse event-related discontinuations. While we commend the authors for their rigorous evaluation, we would like to address a critical aspect of the prostacyclin pathway and propose an alternative approach to maximize the therapeutic potential of oral treprostinil while minimizing its drawbacks.
The reported odds ratio (OR) of 4.39 for adverse events leading to treatment discontinuation is a striking finding, underscoring the trade-offs between efficacy and tolerability. We believe that these outcomes could be partially explained by the clinical setting in which oral treprostinil is often initiated. In advanced stages of PAH, significant arterial fibrosis compromises the functionality of the prostacyclin pathway in the pulmonary arterial bed. Consequently, achieving therapeutic effects often necessitates higher doses of oral treprostinil. Unfortunately, at such doses, the systemic arterial endothelial system – where the prostacyclin pathway remains active – becomes a primary site of adverse effects, leading to increased intolerance.
In light of these observations, we advocate for consideration of initiating oral treprostinil therapy earlier in the disease course. In early-stage PAH, when the prostacyclin pathway is still viable, lower doses of the drug may improve its efficacy by supporting vascular tone and preventing disease progression while avoiding dose-related systemic side effects. This strategy is consistent with the findings of a recent study [2] suggesting that arterial stiffness correlates with deteriorations in hemodynamic and clinical parameters, which worsen with disease progression. Early intervention may help preserve vascular function before significant arterial fibrosis occurs, emphasizing the importance of initiating therapy when the pulmonary arterial bed remains responsive.
The benefits of early intervention in PAH have been demonstrated in several studies. For instance, Boucly et al. [3] found that early and aggressive treatment strategies are associated with improved long-term survival in PAH patients. Similarly, the GRIPHON trial [4] demonstrated that early initiation of prostacyclin pathway agents, such as selexipag, significantly reduced the risk of clinical worsening in PAH patients. These findings underscore the importance of early therapeutic intervention to slow disease progression and improve outcomes.
We believe that further research is essential to demonstrate the benefits of supporting the prostacyclin pathway in early stages of PAH and initiating oral treprostinil therapy during these phases. Studies focusing on early intervention could provide critical insights into optimizing patient outcomes by preserving vascular integrity and preventing disease progression.
