Early Treatment May Help Prevent PAH in High-Risk Patients

Long-term follow-up data from a randomized controlled trial suggest that early treatment can help prevent pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) and early pulmonary vascular disease (PVD).¹

Initial data from the EDITA study, published in 2019, showed improvement in pulmonary vascular resistance but no significant improvement in mean pulmonary arterial pressure (mPAP) compared with placebo after 6 months of treatment with ambrisentan.² These new findings, published in Arthritis Research & Therapy, tracked the effects of treatment, and lack thereof, for an average of 2.5 years.

“Early detection of PVD, before the progress to a severe impairment of hemodynamics, leads to improvement of survival in this population,” explained the researchers. “Although survival of patients with PAH has overall improved in the last decades, the mortality rate of SSc-associated PAH patients still remains high.”

New data from the single-center, open-label extension study, EDITA-ON, suggest that early treatment could benefit these high-risk patients. The study included 34 of the 38 patients from the EDITA study who subsequently received prolonged treatment with ambrisentan or opted to receive no treatment. Nineteen patients received ambrisentan treatment, 8 of whom continued treatment from EDITA and 11 of whom switched from placebo. The other 15 patients elected not to receive treatment.

EDITA-ON, an open-label extension study of the EDITA trial, included 34 of the 38 patients from the EDITA study, 19 of whom received ambrisentan, 8 of whom continued treatment from EDITA, and 11 of whom switched from placebo. | Image Credit: Angelov-stock.adobe.com

After a median 2.36 years, 17 patients receiving ambrisentan and 12 patients not receiving treatment underwent right heart catheterization. None of the 17 treated patients developed PAH throughout follow-up, while 4 patients not on treatment developed PAH (P < .0001). Based on the finding, the researchers noted that the decision to discontinue PAH targeted therapy should be done with caution in high-risk patients.

Development of PAH was based on newer European Society of Cardiology and European Respiratory Society guidelines from 2022.³ Using older, 2016 guidelines, only 2 patients would have been diagnosed with PAH at the end of long-term follow-up. Updates made to the guidelines in 2022 are grounded in earlier identification of patients with earlier stages of PAH.

Patients receiving ambrisentan had significant mean (SD) improvements in mPAP compared with patients not receiving treatment (–1.53 [2.53] vs 1.91 [2.98] mm Hg; P = .003). All patients receiving the PAH medication experienced a reduction in mPAP, while no untreated patients experienced a reduction. Notably, at last follow-up 5 patients receiving ambrisentan showed improvements in hemodynamics, exhibiting no signs of PVD.

The researchers cautioned against generalizations extracted from their findings due to the study being limited to a single center and retrospective in nature. Because patients knew of their treatment, or lack thereof, the researchers also noted the possibility of biased results.

There were no other significant differences in hemodynamic parameters between the 2 groups, during rest and exercise.

“This could be partly due to the mild disease, the impaired walking capability caused by arthralgia in some patients, and the small study population,” wrote the researchers. “Clinical worsening of PH [pulmonary hypertension]/PAH defined by hospitalization was not reported by any of the patients, although worsening of hemodynamics is usually accompanied with clinical deterioration. In this current study, SSc patients were diagnosed early and were treated at a stage prior to further deterioration of hemodynamics. Thus, an early treatment decision assisted and may have prevented the manifestation of PAH.”

The group also assessed the safety and tolerability of treatment, finding no severe adverse events or treatment discontinuation among those receiving ambrisentan.

References

1. Xanthouli P, Uesbeck P, Lorenz H-M, 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. Published online July 18, 2024. doi:10.1186/s13075-024-03363-0

2. Pan Z, Marra AM, Benjamin N, 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;21(1):217. doi:10.1186/s13075-019-1981-0

3. Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). European Respiratory Journal. 2022. Accessed July 23, 2024. https://erj.ersjournals.com/content/erj/early/2022/08/25/13993003.00879-2022.full.pdf