Benefit of upfront combination therapy not seen in low-risk PAH

Key takeaways:

• Ambrisentan-tadalafil therapy was beneficial in patients with intermediate/high-risk PAH, not low-risk PAH.
• More low-risk patients receiving combination therapy vs. monotherapy withdrew due to side effects.

Upfront combination therapy for patients with low-risk pulmonary arterial hypertension was not significantly better than monotherapy when assessing time to clinical worsening, according to results published in CHEST.

“For the time being, we need to follow the current European guidelines and begin with a dual combination therapy from the outset for all patients diagnosed with PAH,” Charles Fauvel, MD, cardiologist and clinical research fellow at The Ohio State University, told Healio. “Nevertheless, these results should prompt the PH community to ask questions and set up a randomized controlled trial to test this hypothesis.”

In this study, Fauvel and colleagues assessed 500 patients (median age, 57 years; 78% women) with PAH from the AMBITION trial, which recommended upfront ambrisentan-tadalafil therapy for treatment-naive, low-risk disease patients, to see if upfront combination therapy prolongs time to clinical worsening compared with monotherapy (either ambrisentan or tadalafil) in this risk group.

Notably, clinical worsening was made up of three factors: death, hospitalization due to worsening PAH and disease progression.

Researchers used two tools to group patients according to their risk level. The Registry to Evaluate Early and Long-term PAH Disease Management 2.0 (REVEAL 2.0) score classified 187 patients as having low-risk PAH, whereas the Pulmonary Hypertension Outcomes and Risk Assessment (PHORA) classified 234 patients with low-risk PAH.

Between baseline and week 16 of treatment in patients with low-risk PAH, researchers noted a similar proportion of patients in the upfront combination therapy group and the monotherapy group with a worsened PAH risk assessment in the REVEAL 2.0 cohort and the PHORA cohort.

In the low-risk REVEAL 2.0 cohort, 100 patients received upfront combination therapy and the remaining 87 patients received monotherapy. Through Cox proportional analysis, researchers found that time to clinical worsening was not significantly better in the combination therapy vs. monotherapy group at 1 year or 3 years after enrollment.

In the low-risk PHORA cohort, 114 patients received upfront combination therapy and 120 received monotherapy. Similar to the above results, time to clinical worsening was not significantly better among those who received upfront combination therapy vs. monotherapy at 1 year or 3 years.

There was no significant difference in the proportion of patients with low-risk PAH receiving upfront combination therapy vs. monotherapy who withdrew due to a side effect; however, more patients in the combination group reported withdrawing (REVEAL 2.0 cohort, 13% vs. 9.2%; PHORA cohort, 13.2% vs. 7.5%).

When researchers considered time to clinical worsening or side effects, upfront combination therapy in low-risk patients continued to show no significant benefit over monotherapy in both risk tool cohorts.

“Until now, there have been no studies using modern risk stratification tools to show that low-risk patients might not benefit from dual therapy,” Fauvel told Healio.

Within the group of patients with intermediate/high-risk PAH based on REVEAL 2.0 (n = 313), time to clinician worsening was significantly better among those who received upfront combination therapy (n = 153) vs. those who received monotherapy (n = 160) at both 1 year (HR = 0.34; 95% CI, 0.17-0.67) and 3 years (HR = 0.59; 95% CI, 0.38-0.92) after enrollment.

Researchers noted comparable findings in the intermediate/high-risk PHORA cohort (n = 266), with significant benefit found with combination therapy (n = 139) vs. monotherapy (n = 127) in terms of time to clinical worsening at 1 year (HR = 0.29; 95% CI, 0.14-0.59) and 3 years (HR = 0.49; 95% CI, 0.31-0.8).

Upfront combination therapy continued to show that it was significantly better than monotherapy among individuals with intermediate/high-risk PAH when researchers evaluated time to clinical worsening or side effects in the PHORA cohort at 1 year (HR = 0.56; 95% CI, 0.33-0.95) and 3 years (HR = 0.6; 95% CI, 0.39-0.94) after enrollment.

“This study suggests that in the future, studies will have to take risk stratification into account in addition to the usual inclusion criteria, as it seems that this will have an impact on the therapeutic strategy to be implemented,” Fauvel said.