Rationale: The aromatase inhibitor anastrozole blocks the conversion of androgens to estrogen and blunts pulmonary hypertension in animals, but its efficacy in treating patients with pulmonary arterial hypertension (PAH) is unknown.

Objectives: We aimed to determine the safety and efficacy of anastrozole in PAH.

Methods: We performed a randomized, double-blind, placebo-controlled trial of anastrozole in patients with PAH who received background therapy at two centers.

Measurements and Main Results: A total of 18 patients with PAH were randomized to anastrozole 1 mg or matching placebo in a 2:1 ratio. The two co–primary outcomes were percent change from baseline in 17β-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: −40%; interquartile range [IQR], −61 to −26% vs. −4%; IQR, −14 to +4%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = +26 m) compared with placebo (median change = −12 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo −2%; IQR, −7 to +1%; P = 0.042). Anastrozole had no effect on circulating biomarkers, functional class, or health-related quality of life. There was no difference in adverse events.

Conclusions: Anastrozole significantly reduced E2 levels in patients with PAH but had no effect on TAPSE. Anastrozole was safe, well tolerated, and improved 6-minute-walk distance in this small “proof-of-principle” study. Larger and longer phase II clinical trials of anastrozole may be warranted in patients with PAH.

Clinical trial registered with www.clinicaltrials.gov (NCT 1545336).