Age Predicts How Well Patients with Pulmonary Arterial Hypertension Respond to Different Drug Classes

Research has shown that combination drug therapy — using agents that target different pathways — can improve long-term clinical outcomes in patients with pulmonary arterial hypertension (PAH).

Specifically, the AMBITION trial (a Randomised, Multicenter Study of First-Line Ambrisentan and Tadalafil Combination Therapy in Subjects with Pulmonary Arterial Hypertension) found delayed PAH hospitalizations with this approach. Criticisms of the AMBITION trial, however, include increased side effects and a lack of specific comparative long-term survival outcome data.

With this in mind, researchers recently undertook a retrospective study to ascertain baseline characteristics of patients that could help predict response to one particular class of therapy — either an endothelin receptor antagonist (ERA) or phosphodiesterase-5 inhibitor (PDE5i).

“In PAH studies there has not been any head-to-head comparison between these two drugs regarding long-term survival,” says Gustavo Heresi, MD, of Cleveland Clinic’s Department of Pulmonary Medicine, and an author of the study published in the American Journal of Respiratory and Critical Care Medicine.

“It is quite unlikely that any such head-to-head comparison will be conducted,” he says, “and so the only way to answer that question of which one may be more effective as measured by long-term survival was through a retrospective cohort study.”

Studying medical records of patients with PAH

Dr. Heresi and colleagues looked at the medical records of 237 PAH patients, of which 91 were initially treated with an ERA and 146 with a PDE5i. In the ERA group, 81 (89 percent) received bosentan, five (5.5 percent) received ambrisentan and five received macitentan. In the PDE5i group, 121 (82.9 percent) were treated with sildenafil and 25 (17.1 percent) with tadalafil.

Fourty-four (48.4 percent) ERA patients were on monotherapy, 32 (35.2 percent) were on dual therapy, 14 (15.4 percent) were on triple therapy and nine (9.9 percent) were on parenteral prostacyclin at the end of follow-up. Among patients who received PDE5i, 79 (54.1 percent) were on monotherapy at last follow-up, 43 (29.5 percent) were on dual therapy, 18 (12.3 percent) were on triple therapy, and 11 (7.5 percent) were on parenteral prostacyclin.

Investigators followed patients for a median of 1,304 days. There were 48 deaths (52.7 percent) in the group who received ERAs and 71 (48.6 percent) in the PDE5i group.

Different drugs for different ages

The researchers found no difference in mortality between the two groups. After adjusting for treatment exposure, sex, race, BMI and the linear propensity score, they found a significant interaction between age and therapeutic agent used in relation to survival.

“We were trying to find baseline clinical characteristics of the patients that may make them more responsive to one treatment versus the other,” says Dr. Heresi. “In doing that, we found that long-term survival is modified by age, where the younger persons (under age 45) treated with an ERA had better long-term survival and older patients (above age 65) treated with PDE5i had better survival.”

He says the fact that older patients fared better with a PDE5i likely had to do with a common comorbidity, left ventricular diastolic dysfunction. Research has shown that ERAs can be detrimental to patients with this condition, whereas a PDE5i can be more benign. However, he says, the researchers don’t have an answer for why younger patients fared better with ERA monotherapy.

“Our study provides an alternative to the AMBITION trial by offering a more individualized treatment approach, where younger people can be started with monotherapy using an ERA and older people can be started with monotherapy using a PDE5 inhibitor.”