Primary Prevention of Cardiovascular Disease With HRT

Kate Maclaran; John C Stevenson


Women's Health. 2012;8(1):63-74. 

In This Article

Cardiovascular Effects of Other Compounds With Estrogenic Properties


Tibolone is a synthetic molecule combining estrogenic, progestogenic and androgenic activity, often used for management of menopausal symptoms and prevention of postmenopausal osteoporosis. Tibolone has been shown to have favorable effects on lipid profile in postmenopausal women, resulting in reductions in total cholesterol, lipoprotein (a) and triglyceride:HDL ratio.[77] However, in contrast to estrogen therapy, tibolone is associated with reductions in HDL cholesterol,[77,78] which may be detrimental to cardiovascular risk. Animal studies have demonstrated a beneficial effect of tibolone on atherosclerosis prevention;[79,80] however, studies of surrogate markers such as endothelial function in postmenopausal women have been contradictory.[77,81] The OPAL study was a clinical trial designed to study the cardiovascular effects of tibolone, in which 866 healthy postmenopausal women were randomized to tibolone 2.5 mg daily, CEE/MPA or placebo for 3 years.[78] This study found an increased progression of carotid artery IMT in both tibolone and CEE/MPA groups compared with placebo, raising concerns that tibolone may have adverse cardiovascular effects. The LIFT study was a randomized, placebo controlled study in 4506 older postmenopausal women (60–85 years) who received 1.25 mg tibolone daily.[82] Secondary outcomes in this study included cardiovascular events. The study was stopped prematurely after a median of 34 months treatment due to an increased risk of stroke in the tibolone group (RR: 2.19, 95% CI: 1.14–4.23), but no increase in coronary events or VTE was observed. Current evidence, therefore, suggests that tibolone may be associated with an increased risk of stroke in older postmenopausal women, but does not appear to adversely affect risk of CHD or VTE.

Selective Estrogen Receptor Modulators

Selective estrogen receptor modulators (SERMs) are compounds that exert varying agonist and antagonist effects on estrogen receptors. Tamoxifen has been available for many years and its estrogen antagonist actions are used in the treatment of breast cancer, although vasomotor symptoms and endometrial hyperplasia can be problematic. Another agent in use is raloxifene, licensed for the prevention and treatment of postmenopausal osteoporosis, but can also adversely affect vasomotor symptoms. This class of drugs has been gaining much interest in recent years with attempts to maximize beneficial effects of estrogen agonism and antagonism while minimizing adverse effects.

Little is know about the long-term effects of the different SERMs on CVD. Data examining coronary events in women on tamoxifen have been conflicting,[83,84] whereas animal studies have shown a benefit on atherosclerosis prevention, although to a lesser extent than that observed with CEE.[85] Raloxifene has been associated with reductions in total and LDL cholesterol,[86] and stimulation of nitric oxide synthetase.[87] The RUTH study was a randomized placebo controlled trial investigating the use of raloxifene in 10,101 women.[88] Overall, they found no effect of raloxifene on coronary events, but there was a significantly increased risk of VTE and stroke. Further analysis of the RUTH data has highlighted the importance of age on cardiovascular outcomes, as the data showed a reduction in coronary events in women younger than 60 years initiating raloxifene treatment (HR: 0.59, 95% CI: 0.41–0.83).[89]

Of the newer third-generation SERMS, lasofoxifene at higher doses (0.5 mg) was associated with a significant reduction in major CHD events after 5 years of therapy (HR: 0.68, 95% CI: 0.5–0.93), but also with increased risk of VTE.[90]

Another new generation SERM, bazedoxifene, has been combined with conjugated estrogen in an attempt to harness beneficial effects on bone and menopausal symptoms while avoiding adverse effects on breast and endometrial tissues. The 2-year safety data has shown no difference in the incidence of cardiovascular events compared with placebo, but event numbers were small and further long-term data are required.[91]


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