Do Patients With Low-Risk Pulmonary Arterial Hypertension Really Benefit From Upfront Combination Therapy?

Background

Based on results of the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension (AMBITION) trial, upfront combination therapy is recommended for treatment-naive patients with low-risk 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 (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 time to clinical worsening at 1 and 3 years' post-enrollment using Cox proportional analysis (3-year hazard ratio 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 time to clinical worsening or side effects (3-year hazard ratio 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, patients at intermediate or high risk 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.