HOUSTON – The novel investigational tissue selective estrogen complex comprising bazedoxifene plus conjugated estrogens displayed an overall favorable coagulation profile in a pooled analysis of three randomized, placebo-controlled, double-blind, phase III clinical trials.
Moreover, the risk of venous thromboembolism or cerebrovascular events was low, at 0.2% or less during up to 2 years of treatment, a rate not significantly different from that of control patients, Dr. Sven O. Skouby of Herlev (Denmark) Hospital said at the annual meeting of the Endocrine Society.
He presented an analysis of serial coagulation parameters obtained in 1,978 postmenopausal women with intact uteri who were randomized to bazedoxifene at 20 mg per day plus either 0.45 or 0.625 mg of conjugated estrogens or to placebo in the first, fourth, and fifth SMART (Selective Estrogens, Menopause, and Response to Therapy) trials. SMART-1 assessed changes in coagulation variables at 12 and 24 months, while SMART-4 and -5 did so at 12 months.
Changes from baseline in protein C activity, d-dimer level, and prothrombin and partial thromboplastin times were similar in the two bazedoxifene/conjugated estrogens study arms and in placebo-treated controls.
The two active treatment arms showed modest but not clinically meaningful decreases in plasminogen activator-1, antithrombin III, and fibrinogen, compared with placebo. Similarly, plasminogen activity in the two active treatment groups increased by a mean of 0.1 L/L over the course of 24 months, a statistically greater increase than the 0.06 L/L seen in the control group, but not a clinically significant difference, Dr. Skouby observed.
SMART-1, -4, and -5 included 3,549 randomized patients with follow-up data on hard clinical thromboembolic events. Three patients on bazedoxifene/conjugated estrogens experienced deep vein thrombosis during 2 years of therapy, as did one on placebo. There were no cases of pulmonary embolism. Two of the treated patients and no controls had a cerebrovascular event.
In a separate presentation, Dr. Sebastian Mirkin reported on a pooled analysis of lipid changes in 4,409 postmenopausal women in SMART-1 through -5.
At 24 months, LDL cholesterol fell by a mean 7.4% from baseline in the bazedoxifene 20 mg/conjugated estrogens 0.45 mg group, and by 8.4% in those on bazedoxifene 20 mg/conjugated estrogens 0.625 mg, compared with a 2% increase in controls.
HDL levels rose by 7.3% in the lower-dose and 7.9% in the higher-dose groups, a significantly greater benefit than the 2.8% increase with placebo. Apolipoprotein B declined by a mean of 0.4% in the lower- and 0.5% in the higher-dose bazedoxifene/conjugated estrogens group, compared with a 4.3% increase in controls.
The one negative was that triglyceride levels increased by 20.3% in the lower- and 18.7% in the higher-dose groups, significantly greater than the 7.1% rise with placebo, reported Dr. Mirkin.
Bazedoxifene is not approved in the United States. Pfizer submitted a new drug application to the Food and Drug Administration in 2006, and in 2007 got an "approvable letter" that asked for more information. There is no public record of Pfizer’s response. Pfizer has announced that it will submit an application to the FDA for the bazedoxifene/conjugated estrogen combination this year.
The SMART trials were sponsored by Pfizer. Dr. Skouby serves as a consultant to the company. Dr. Mirkin is a Pfizer employee.