Ambrisentan, an ETA-selective endothelin receptor antagonist (ERA), improved 6-minute walk distance (6MWD) and delayed clinical worsening in two placebo-controlled, 12-week, pulmonary arterial hypertension studies (ARIES-1 and ARIES-2). Patients receiving placebo or ambrisentan in ARIES-1 or ARIES-2 received ambrisentan treatment in a long-term study (ARIES-E).
Two-year clinical outcomes were examined for 100 patients who received 12 weeks of placebo followed by long-term ambrisentan therapy (PLB/ABS) and 197 patients who received long-term ambrisentan (ABS/ABS) treatment. Data are presented for the approved doses of ambrisentan (5 and 10 mg once-daily) and baseline was defined as the time of randomization in ARIES-1 or ARIES-2.
Baseline characteristics were comparable between the subgroups prior to treatment. The mean change from baseline 6MWD (± SEM) was substantially lower in PLB/ABS group at 1 and 2 years (11 ± 9.6 meters and 10 ± 10.0 meters, respectively) compared to the ABS/ABS group (38 ± 6.0 meters and 30 ± 7.1 meters, respectively). Kaplan-Meier estimates (± SEM) of clinical worsening (percent event-free) were slightly lower in the PLB/ABS group compared to the ABS/ABS group at 1 year (76 ± 4.3% versus 84 ± 2.7%, respectively) but were similar at 2 years of treatment (70 ± 4.7% versus 71 ± 3.4%, respectively). Kaplan-Meier estimates of survival were similar in the PLB/ABS group compared to the ABS/ABS group at 1 year (92 ± 2.8% versus 93 ± 1.9%, respectively) and 2 years (86 ± 3.7% versus 88 ± 2.5%, respectively). Long-term ABS therapy was generally well tolerated and similar between the two groups.
A 12-week delay of ambrisentan treatment resulted in a sustained decrease in 6MWD improvement but did not substantially increase the long-term risk of clinical worsening or death.
Initiation of ambrisentan should not be delayed in patients who are appropriate candidates for ERA therapy.
Aaron Waxman, Consultant fee, speaker bureau, advisory committee, etc. Investigator for Gilead Sciences, United Therapeutics, Pfizer, and EPIX. Advisory board for Gilead Science and United Therapeutics.; No Product/Research Disclosure Information