People with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) — particularly those showing low or intermediate disease risk, typical PAH — benefit most from combination therapy with Letairis (ambrisentan) and Adcirca (tadalafil) than from either therapy alone, according to an exploratory sub-analysis of a Phase 3 clinical trial.
The analysis also highlighted that patients at high risk at diagnosis, and those who remain in the intermediate-risk group or move to high risk at follow-up, may potentially benefit from more advanced therapy.
The data suggested that a simplified risk stratification score at diagnosis may help clinicians make better decisions regarding treatment options. However, larger future studies are needed to confirm its predictive value, the researchers noted.
The study, “Initial combination therapy of ambrisentan and tadalafil in connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) in the modified intention-to-treat population of the AMBITION study: post hoc analysis,” was published in the journal Annals of the Rheumatic Diseases.
PAH can develop as a serious complication of CTD, which includes a range of diseases, such as systemic sclerosis (SSc). People with PAH-CTD, including those with SSc-associated PAH (SSc-PAH), tend to have worse disease outcomes than those with idiopathic PAH — that is, PAH with no apparent cause.
It thus is important to identify the best treatment options and predictors of treatment response for this patient population.
The combination of Letairis and Adcirca is an approved first-line treatment for people with PAH. Ambrisentan is sold under the brand name Letairis by Gilead in the U.S., and as Volibris by GlaxoSmithKline in Europe. Adcirca is sold in Europe by its developer, Eli Lilly, and in the U.S. by United Therapeutics.
This approval also was based on data from a Phase 3 clinical trial called AMBITION (NCT01178073). That trial compared the safety and effectiveness of the combination therapy against either therapy alone in untreated PAH patients with slight-to-marked limitation in physical activity — those in WHO functional class 2 and 3.
AMBITION, which involved more than 600 participants, showed that first-line combination therapy was safe and superior to either therapy alone in people with PAH, including those with PAH-CTD.
These final analyses were set to exclude treated patients with less pronounced hemodynamics, or blood circulation, and/or multiple risk factors for left heart disease — in which the heart’s left ventricle pumps significantly less blood. A total of 29 people with CTD-PAH (19 with SSc-PAH) were left out from these analyses.
Now, the researchers set out to assess whether the combination therapy was superior to either therapy alone in all CTD-PAH patients treated within the AMBITION trial, including those excluded from top-line analyses.
This superiority was mainly based on the time a patient lived until the first clinical failure event. Such events included hospitalization for worsening PAH, disease progression, death, or unsatisfactory long-term clinical response.
The team also evaluated the predictive value of clinical features and risk stratification at diagnosis in terms of responses to single and combination therapy among this specific patient subpopulation.
The risk stratification was based on an abbreviated, three-parameter, non-invasive risk stratification score method of disease outcomes used in previous studies, based on the risk thresholds of the 2015 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines.
This new analysis included 216 people with CTD-PAH (189 women and 27 men) who were randomly assigned to receive the combination therapy (117 patients) or a single therapy (a combined total of 99 patients).
SSc-PAH was present in 137 patients (116 women and 11 men), and this group had a higher mean age (above 60) than the CTD-PAH group (under 60); other disease characteristics were similar between the two groups.
The results showed that the CTD-PAH patients treated with the combination therapy had a 51.7% lower risk of clinical failure, compared with those treated with single therapy. Among the individuals with SSc-PAH, the combo therapy was associated with a 53.7% lower risk.
These combo-associated benefits also were more pronounced among people with hemodynamic features characteristic of typical PAH, and less marked among those with an increased risk of left heart disease and/or reduced lung volumes.
When using the abbreviated risk stratification method, 27 patients (12.5%) were classified as having low-risk disease, with 179 (82.9%) identified as intermediate-risk, and 10 (4.6%) as high-risk at baseline, which was the study’s start.
The data indicated that the combination therapy was more effective in reducing the risk of clinical failure among CTD-PAH patients with low and intermediate risk at baseline, while those with high-risk disease may benefit from more advanced therapy. Similar trends were found for people with SSc-PAH.
“Combination therapy is appropriate for patients with typical PAH categorised as low and intermediate risk at baseline, while high-risk patients could possibly be considered for more advanced therapy,” the researchers said.
Moreover, the team noted that therapy escalation may be recommended in those individuals remaining in the intermediate-risk category or moving to the high-risk category at follow-up.
“A simplified risk stratification score at baseline using non-invasive parameters may be useful in predicting PAH-related outcomes in patients with CTD-PAH,” the researchers said.
They noted, however, that further studies in a larger group of CTD-PAH patients are needed to determine the best predictive tools in terms of applicability and accuracy at baseline and at follow-up.
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