Post-Menopausal Hormone Therapy and Cardiovascular Events: A New Paradigm Based On pharmacogenetics?

Abstract

The risk of coronary heart disease (CHD) events increases in women after menopause and it was thought that hormone therapy (HT) would decrease this risk. However, numerous large randomized clinical trials have not demonstrated decreased risk in secondary prevention and some have actually shown increased risk of cardiovascular events with HT in primary prevention. Platelets are involved in CHD events and platelet glycoprotein single-nucleotide polymorphisms may help to identify risk and treatment efficacy. It may become a plausible strategy in the future for clinicians to identify, by genotyping, high-risk patients who would benefit from HT to reduce CHD risk as well as to identify patients with neutral risk for whom HT could be harmful.In the March 2007 issue of Blood, Bray et al. reported their findings on the effects of singlenucleotide polymorphisms (SNPs) in selected platelet glycoprotein (GP) genes on the risk for coronary heart disease (CHD) events in postmenopausal women with established CHD taking estrogen/progestin hormone therapy (HT) [1]. This is a salient issue as it is well known that the risk of CHD events increase in women after menopause and it was thought that HT would decrease this risk. However, numerous large randomized clinical trials have not demonstrated decreased risk in secondary prevention [2][3][4], and some have actually shown increased risk of cardiovascular events with HT in primary prevention [5,6].Our group was the first to report an association between a platelet GP polymorphism (GPIIIa Pl A2 ) and effect of estrogen on in vitro platelet function. We were intrigued by this clinical data and, in our initial report, we demonstrated that estrogen was a potent antiplatelet, but this effect was only present in Pl A1/A2 individuals, an effect that was interestingly not observed in the presence of aspirin [7]. In a follow-up study, we demonstrated that estrogen concentrations expected in HT resulted in a paradoxical effect depending on genotype, with significantly increased platelet aggregation in Pl A1/A1 individuals and significant inhibition in Pl A1/A2 individuals [8].The Heart and Estrogen/Progestin Replacement Study (HERS) was a randomized, blinded, placebo-controlled secondary prevention trial carried out in 2763 women, aged less than 80 years, with established coronary artery disease (CAD) and was designed to determine if estrogen (0.625 mg, daily) plus progestin (2.5 mg, daily) therapy alters the risk for CHD events [3]. The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack and peripheral arterial disease. Follow-up averaged 4.1 years and, overall, there were no significant differences between groups in the primary outcome (relative hazard [RH]: 0.99; 95% confidence interval [CI]: 0.80-1.22; p = 0.91) or in any of the secondary outcomes. In evaluating events over t...