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Inflammatory, Lipid, Thrombotic, and Genetic Markers of Coronary Heart Disease Risk in the Women's Health Initiative Trials of Hormone Therapy
Jacques E. Rossouw, MD;
Mary Cushman, MD, MSc;
Philip Greenland, MD;
Donald M. Lloyd-Jones, MD;
Paul Bray, MD;
Charles Kooperberg, PhD;
Mary Pettinger, MS;
Jennifer Robinson, MD;
Susan Hendrix, DO;
Judith Hsia, MD
Arch Intern Med. 2008;168(20):2245-2253.
Background Clinical trials of postmenopausal hormone therapy (HT) have shown increased risk of coronary heart disease (CHD) in the first few years after initiation of therapy and no overall benefit.
Methods This nested case-control study evaluates a range of inflammatory, lipid, thrombotic, and genetic markers for their association with CHD in the 4 years after randomization and assesses whether any of these markers modified or mediated the initially increased risk associated with HT in postmenopausal women aged 50 to 79 years at baseline. Conjugated equine estrogens, 0.625 mg/d, or placebo was given to 10 739 hysterectomized women, and the same estrogen plus medroxyprogesterone acetate, 2.5 mg/d, was given to 16 608 women with an intact uterus.
Results In multivariate-adjusted analyses of 359 cases and 820 controls in the combined trials, baseline levels of 12 of the 23 biomarkers studied were associated with CHD events: interleukin 6, matrix metalloproteinase 9, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, total cholesterol, triglycerides, D-dimer, factor VIII, von Willebrand factor, leukocyte count, homocysteine, and fasting insulin. Biomarkers tended to be more strongly associated with CHD in the initial 2 years after randomization. The genetic polymorphism glycoprotein IIIa leu33pro was significantly associated with CHD. Baseline low-density lipoprotein cholesterol interacted significantly with HT so that women with higher levels were at higher risk for CHD when given HT (P = .03 for interaction). The levels of several biomarkers were changed by HT, but these changes did not seem to be associated with future CHD events.
Conclusions Several thrombotic, inflammatory, and lipid biomarkers were associated with CHD events in postmenopausal women, but only low-density lipoprotein cholesterol modified the effect of HT. Further research is needed to identify the mechanisms by which HT increases the risk of CHD.
Trial Registration clinicaltrials.gov Identifier: NCT00000611
Author Affiliations: Women's Health Initiative Branch, Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, Maryland (Dr Rossouw); Departments of Medicine and Pathology, University of Vermont, Burlington (Dr Cushman); Department of Preventive Medicine, Northwestern University, Chicago, Illinois (Drs Greenland and Lloyd-Jones); Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania (Dr Bray); Fred Hutchinson Cancer Research Center, Seattle, Washington (Dr Kooperberg and Ms Pettinger); Department of Epidemiology, University of Iowa, Iowa City (Dr Robinson); Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan (Dr Hendrix); and Department of Medicine, George Washington University, Washington, DC (Dr Hsia). Dr Hsia is now with AstraZeneca, Wilmington, Delaware.
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