Do low-risk pulmonary arterial hypertension patients really benefit from upfront combination therapy. insight from the AMBITION trial

Background: Based on results of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, upfront combination therapy is recommended for "low-risk" treatment-naive patients with pulmonary arterial hypertension (PAH). However, conflicting data exist whether adopting this treatment strategy in this risk group is beneficial or well tolerated. Research question: Do patients with low-risk PAH really benefit from upfront combination therapy? Study design and methods: Using the data from the original AMBITION trial, patients with PAH were classified as low, intermediate, or high risk using the Registry to Evaluate Early and Long-term PAH Disease Management 2.0 (REVEAL 2.0) score and the Pulmonary Hypertension Outcomes and Risk Assessment (PHORA) tool. The primary end point was time to clinical worsening (TTCW; including death, hospitalization for PAH worsening, and disease progression) censored at 1- and 3-year post-enrollment. Side effects that led to withdrawal of treatment were also considered. Results: Patients with low-risk PAH categorized by REVEAL 2.0 and PHORA did not see a statistically significant benefit of upfront combination therapy vs monotherapy for TTCW at 1 and 3 years' post-enrollment using Cox proportional analysis (3-year hazard ratio [HR] of 0.40 [95% CI, 0.15-1.06; P = .07] and 0.55 [95% CI, 0.26-1.18; P = .12] for REVEAL 2.0 and PHORA, respectively) or considering TTCW or side effects (3-year HR of 0.75 [95% CI, 0.39-1.47; P = .4] and 0.87 [95% CI, 0.49-1.54; P = .63] for REVEAL 2.0 and PHORA). Patients with low-risk PAH on upfront combination therapy experienced a higher but not significant incidence of side effects using REVEAL 2.0 and PHORA. In contrast, intermediate- or high-risk patients saw a statistically significant benefit of upfront combination therapy considering each of the end points regardless of side effects. Interpretation: This analysis suggests that perhaps some patients with low-risk PAH should be further stratified using other modalities prior to committing to upfront combination therapy, especially when the occurrence of side effects is considered. Further prospective data are needed to validate this hypothesis prior to changes in current guideline directed therapy are contemplated.