Treatment Strategies for Achieving and Maintaining Low-Risk Status in Pulmonary Arterial Hypertension: A Systematic Review.

Achieving and maintaining low-risk status is now the main treatment goal in pulmonary arterial hypertension (PAH), but the evidence connecting individual treatment strategies with low-risk attainment and long-term outcomes is scattered across trials, registries, and cohorts that use different risk tools. We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. PubMed, Scopus, Dimensions, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to August 27, 2026, for studies of adults with Group 1 PAH that evaluated a treatment strategy and reported a validated risk-stratification outcome. Results were synthesised narratively under the Synthesis Without Meta-analysis (SWiM) guideline, with certainty graded using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Forty-eight reports were included: 10 randomised or prospective interventional studies, 12 secondary analyses of trial data, and 26 observational cohorts. Few patients reached low risk under any strategy, and fewer than half did so after upfront dual oral therapy in most cohorts. Prostacyclin-pathway therapy improved risk status across oral, inhaled, and parenteral routes, although the clearest survival advantage came from parenteral regimens in registry data. Add-on sotatercept improved functional, haemodynamic, and composite clinical outcomes, and these gains were largely sustained at one year. Low-risk status predicted survival, yet it often did not last, and the risk category reached at the first annual review strongly predicted later course. In mediation analyses, change in risk score accounted for only part of the treatment effect, and studies disagreed on whether patients already at low risk benefit from further treatment. Low-risk status is a valuable treatment target and prognostic marker, but it has not been validated as a surrogate endpoint. Early, repeated risk assessment and prompt escalation during the first year after diagnosis are supported by the available evidence.