Ambrisentan reduces risk of pulmonary arterial hypertension in systemic sclerosis patients, study finds

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A new study, EDITA-ON, published in Arthritis Research & Therapy has found that continued treatment with ambrisentan significantly lowers the risk of developing pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) and early-stage pulmonary vascular disease (PVD). The findings suggest that early intervention with this therapy, along with close monitoring, may offer substantial benefits for this high-risk patient population. 

The EDITA trial, conducted prior to EDITA-ON, had already shown that ambrisentan was effective in reducing pulmonary vascular resistance (PVR) in SSc patients with mild PVD. However, the treatment did not lead to a significant reduction in mean pulmonary arterial pressure (mPAP) when compared to placebo after six months. Building on these initial results, the EDITA-ON study aimed to assess the long-term impact of ambrisentan on preventing the progression to PAH. 

The study enrolled 38 SSc patients who had participated in the previous EDITA trial, with 34 completing the follow-up period. Of these, 19 patients continued receiving ambrisentan after the blinded phase, while 15 patients received no PAH medication. The primary objective was to determine whether ongoing treatment with ambrisentan could prevent the development of PAH, as defined by updated diagnostic criteria. A range of clinical, echocardiographic, laboratory, exercise, and hemodynamic parameters were assessed over a median follow-up period of 2.59 ± 1.47 years. During this period, 29 patients underwent right heart catheterization to monitor changes in pulmonary hemodynamics. 

Patients treated with ambrisentan showed a significant improvement in mPAP, with a decrease of -1.53 ± 2.53 mmHg compared to an increase of +1.91 ± 2.98 mmHg in those who did not receive treatment (p = 0.003). Additionally, the incidence of PAH was substantially lower in the ambrisentan group. While 6 out of 12 patients (50%) in the no-treatment group developed PAH, only 1 out of 17 patients (5.9%) in the ambrisentan group experienced the same outcome (p < 0.0001). 

Ambrisentan, an endothelin receptor antagonist, is a vasodilator that specifically targets and inhibits the endothelin type A (ETA) receptor, thereby preventing vasoconstriction. By selectively blocking the ETA receptor, ambrisentan inhibits phospholipase C-mediated vasoconstriction and protein kinase C-mediated cell proliferation. It does not significantly affect the function of the endothelin type B (ETB) receptor, allowing for the preservation of nitric oxide and prostacyclin production, as well as cyclic GMP- and cyclic AMP-mediated vasodilation and endothelin-1 (ET-1) clearance. 

A randomized, double-blind, placebo-controlled trial conducted by Pan et al. assessed the effects of ambrisentan in patients with mildly elevated mPAP and/or exercise-induced PH. While the study showed a trend toward improvement in mPAP in the ambrisentan group, significant improvements in other hemodynamic parameters suggest a potential benefit of ambrisentan. 

These findings suggest that continued ambrisentan therapy can significantly reduce the progression to PAH and improve pulmonary vascular function in patients with early-stage PVD. The results emphasize the importance of early treatment and close monitoring to prevent the deterioration of pulmonary function in SSc patients, who are at high risk for PAH. 

The study opens the door for further research to explore the long-term benefits of ambrisentan therapy. As PAH remains a leading cause of morbidity and mortality in SSc patients, future trials will be essential to confirm these findings and identify the most effective treatment strategies for this vulnerable population. 

 

Reference 

  1. Xanthouli P, Uesbeck P, Lorenz HM, Blank N, Eichstaedt CA, Harutyunova S, et al. Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study. Arthritis Res Ther. 2024 Jul 18;26(1):136. 
  2. Ambrisentan: Uses, Interactions, Mechanism of Action | DrugBank Online [Internet]. [cited 2024 Dec 3]. Available from: https://go.drugbank.com/drugs/DB06403 
  3. Pan Z, Marra AM, Benjamin N, Eichstaedt CA, Blank N, Bossone E, et al. Early treatment with ambrisentan of mildly elevated mean pulmonary arterial pressure associated with systemic sclerosis: a randomized, controlled, double-blind, parallel group study (EDITA study). Arthritis Res Ther. 2019 Oct 26;21(1):217.Â