Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial

Abstract

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, placebocontrolled 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 17b-estradiol levels (E2) and tricuspid annular plane systolic excursion (TAPSE) at 3 months. Anastrozole significantly reduced E2 levels compared with placebo (percent change: 240%; interquartile range [IQR], 261 to 226% vs. 24%; IQR, 214 to 14%; P = 0.003), but there was no difference in TAPSE. Anastrozole significantly increased the 6-minute-walk distance (median change = 126 m) compared with placebo (median change = 212 m) (median percent change: anastrozole group, 8%; IQR, 2 to 17% vs. placebo 22%; IQR, 27 to 11%; 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).

Pulmonary Hypertension in Pregnancy

“…30 We have previously shown that increased levels of circulating estradiol are associated with a more than 50-fold increase in the risk of PAH in men and with worse pulmonary vascular disease burden, 31 and that therapeutic strategies aimed at reducing estrogen exposure (e.g., via anastrozole) may be beneficial in men and women with PAH. 32 While sex hormone levels and genetic variation in sex hormone pathways have been linked to RV function in health 33,34 and in a limited way to PAH, 35,36 the effects of these hormones and their fluctuations during and after pregnancy in PAH (and to a large extent in healthy women) are unknown.…”

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

“…Preliminary data in female Su-Hx rats (published in abstract form [54]) suggest that despite reducing PH and the number of occlusive lesions, anastrozole does not reduce RV hypertrophy, as would be expected from reduced occlusive remodeling and reduced afterload. Finally, although anastrazole on average had no effects on echocardiographic parameters and biomarkers of RV function in the proof-of-concept study on PAH, anastrazole had varying effects on individual patients' RV function, with some experiencing worsening in RV function [59].…”

“…Collectively, the experimental and observational data point toward a potential use of ARO-I in PH. Indeed, in a recent pilot phase 2 clinical trial in postmenopausal women and men with PAH, Kawut et al reported that 12-week treatment with anastrozole reduced serum E2 levels by 40% and E1 levels by 70%, and significantly increased 6MWD [59].…”

Inhibiting oestrogen signalling in pulmonary arterial hypertension: sex, drugs and research

“…Similarly, oestrogen receptor-mediated signalling has been linked to PAH development [8]. These studies have led to a recently published, small phase II randomised clinical trial (RCT) of aromatase inhibition with anastrozole in postmenopausal women and men with PAH [10]. This study demonstrated that anastrozole decreased serum E2 levels by 40% and increased 6-min walk distance, leading the authors to conclude that anastrozole therapy appeared safe and warranted further evaluation.…”

“…Based on the results of the pilot human trial [10] and recent experimental studies in a model of more severe PAH [6], a phase II study of anastrozole is currently underway. Could other strategies for inhibiting oestrogenic signalling be beneficial?…”