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WHI: Several thrombotic, inflammatory, lipid, genetic biomarkers linked with CHD
LDL modified the effect of HT in postmenopausal women.
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A new analysis of a subset of postmenopausal women enrolled in the Women’s Health Initiative trials of hormone therapy revealed significant associations with coronary heart disease and 12 of 23 biomarkers studied.
LDL was the only biomarker and glycoprotein IIIa leu33pro the only genetic marker studied that modified the effect of HT in women enrolled in the WHI.
Researchers conducted a nested case-control study to examine the association between specific genetic, inflammatory, lipid and thrombotic markers and CHD four years after being randomly assigned to HT. The researchers randomly assigned 10,739 women who had hysterectomies to conjugated equine estrogens (Premarin, Wyeth) 0.625 mg per day or placebo, and assigned 16,608 women with an intact uterus to conjugated equine estrogens 0.626 mg per day plus medroxyprogesterone acetate (Prempro, Wyeth) 2.5 mg per day. This multivariate analysis included 359 cases and 820 controls in the combined trials.
The results were published in the Archives of Internal Medicine.
Baseline levels of several biomarkers were associated with CHD events within the initial two years after being randomly assigned to HT: interleukin-6, matrix metalloproteinase 9, D-dimer, factor VIII, von Willebrand’s factor, leukocyte count, homocysteine, fasting insulin, triglycerides, total cholesterol, HDL and LDL (see table).
Association Between Biomarkers and Risk for Coronary Heart Disease in the Women's Health Initiative Trials of Hormone Therapy |
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The researchers reported a significant interaction between baseline LDL and HT; women receiving HT with higher levels of LDL cholesterol were at higher risk for CHD (P=.03).
“This investigation did not identify any novel biomarkers or gene polymorphisms that might be clinically useful for identifying women at increased risk if they undergo postmenopausal HT. Further research is needed to better individualize HT. However, it might be useful to measure the lipid profile before prescribing HT because high LDL cholesterol levels are associated with increased risk for CHD for women starting HT,” the researchers wrote. – by Katie Kalvaitis
Arch Intern Med. 2008;168:2245-2253.
Ever since the publication of the Heart and Estrogen/Progestin Replacement Study (HERS) a decade ago, the hunch persists that there must be a unique identifying characteristic that predicts which women will be at high risk for CHD events when HT is initiated. The HERS investigators reported that high LDL and low HDL levels at baseline predicted subsequent primary CHD events. In the 2003 analysis by Manson et al. (N Engl J Med. 2003;349:523-534) of the CHD risk in the WHI estrogen plus progestin arm of the study, women with higher baseline LDL cholesterol levels (>155 mg/dL) appeared to have a 68% greater excess risk for CHD with HT (after adjustment for age, year of randomization, previous CHD and use of statins at baseline). Given that so many comparisons had been completed in the analysis, however, the authors speculated that the relationship with LDL might be due to chance. Earlier this year, Bray and colleagues conducted a nested case-control study of WHI participants, including both combined therapy and unopposed estrogen arms of the trial (Am J Cardiol. 2008;101:1599-1605). He also reported that lipid status at baseline predicted CHD outcomes. Specifically, women with an LDL/HDL ratio <2.5 had no increase in risk for CHD when starting conjugated equine estrogens with or without medroxyprogesterone acetate, whereas women with a ratio >2.5 had a 73% increase in risk. Rossouw, et al. take this one step further. While a number of thrombotic, inflammatory, lipid and genetic biomarkers were associated with CHD events, only baseline LDL significantly modified the effect of HT. The authors speculate that women with high LDL or low HDL have more subclinical coronary artery disease and consequently more adverse response to HT. Given the consistent findings of these analyses, it seems prudent to measure the LDL/HDL ratio prior to initiating HT in your postmenopausal patients. Depending upon the anticipated risks and benefits in an individual women, proceed with caution if her LDL/HDL ratio is >2.5 or her LDL is >155. This analysis provides one more piece to the puzzle of HT and the heart and potentially confirms a tool to help identify symptomatic women for whom HT will be safe.
– Cynthia A. Stuenkel, MD
Clinical Professor of Medicine, Endocrinology and Metabolism,
University of California, San Diego