In patients with low-risk pulmonary arterial hypertension (PAH), the overall benefit-risk tradeoff of using upfront combination therapy is less convincing than originally thought, according to findings from a post hoc analysis of the randomized controlled AMBrIsentan and Tadalafil in Patients with Pulmonary Arterial HypertensION (AMBITION) trial, published in Chest.

Although the results of AMBITION recommended upfront combination therapy for individuals with low-risk, treatment-naive PAH, current data are debatable as to whether adoption of this approach in this patient population is well tolerated and beneficial.

Based on current guidelines, treatment strategies for patients with PAH are determined according to risk stratification at the time of initiation of therapy and throughout the disease course. In low- and intermediate-risk individuals in whom the estimated 1-year survival is 95% and 80%, respectively, treatment with an oral upfront combination therapy is considered the recommended approach.

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The researchers sought to establish whether low-risk patients with PAH actually do derive a benefit from upfront combination therapy compared with the use of monotherapy. Using data from the original AMBITION trial, they classified patients as low-, intermediate-, and high-risk per the following 2 risk assessment tools:

  • Registry to Evaluate Early and Long-term Pulmonary Arterial Disease Management (REVEAL) 2.0 score
  • Pulmonary Hypertension Outcome and Risk Assessment (PHORA)

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The primary study endpoint was time to clinical worsening, which was defined by death, hospitalization because of worsening PAH, or disease progression, and was censored at the 1- and 3-year postenrollment period. Additionally, side effects were evaluated for drug safety.

In the original AMBITION trial, treatment-naive patients with PAH were assigned to treatment with upfront combination therapy (ie, ambrisentan plus tadalafil) or monotherapy (ie, ambrisentan or tadalafil).

The current analysis enrolled 500 patients with PAH. The median patient age was 57 years (range, 44-67 years). Overall, 78% of the patients were female, 53% had idiopathic PAH, and 69% were considered New York Heart Association functional class III at baseline.

Based on the REVEAL 2.0 tool, 37.4% (187 of 500) of the participants were classified as low-risk and 62.6% (313 of 500) were classified as intermediate- or high-risk at baseline. According to the PHORA tool, 46.8% (234 of 500) of the participants were classified as low-risk and 53.2% (266 of 500) of them were classified as intermediate- or high-risk at baseline.

Using REVEAL 2.0 or PHORA at baseline, the majority of participants were considered to be low-risk individuals at reassessment (P <.001). The REVEAL 2.0 tool exhibited good discrimination capacity for 1-year survival both at baseline and at the 16-week follow-up (C-indices of 0.76 and 0.72, respectively). The PHORA tool exhibited good discriminatory ability at baseline (area under the curve [AUC], 0.70) and excellent discriminatory capacity at the 16-week reassessment (AUC, 0.81).

In spite of a trend in the data using REVEAL 2.0, neither of the low-risk groups determined by REVEAL 2.0 or PHORA demonstrated a statistically significant benefit with upfront combination therapy when censored at 1 or 3 years for time to clinical worsening. In contrast, individuals classified by REVEAL 2.0 or PHORA as intermediate- or high-risk benefited significantly from the use of upfront combination therapy compared with monotherapy.

“Real-world data and then additional randomized clinical trial[s] should be leveraged to further investigate concerns regarding the risk-benefit tradeoff of upfront combination therapy versus sequential add-on therapy or strategic dosing in low-risk patients with PAH,” the researchers concluded.


Fauvel C, Liu Y, Correa-Jaque P, et al. Do low-risk pulmonary arterial hypertension patients really benefit from upfront combination therapy? Insight from the AMBITION trial. Chest. Published online June 23, 2023. doi:10.1016/j.chest.2023.06.023