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Prospective Analysis From the Women's Health Initiative Observational Study

Aruna D. Pradhan, MD, MPH; JoAnn E. Manson, MD, DrPH; Jacques E. Rossouw, MD; David S. Siscovick, MD, MPH; Charles P. Mouton, MD, MS; Nader Rifai, PhD; Robert B. Wallace, MD; Rebecca D. Jackson, MD; Mary B. Pettinger, MS; Paul M Ridker, MD, MPH

JAMA. 2002;288:980-987.

Context  Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown.

Objectives  To assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD) and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk.

Design, Setting, and Participants  Prospective, nested case-control study of postmenopausal women, forming part of the Women's Health Initiative, a large, nationwide, observational study. Among 75 343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years.

Main Outcome Measure  Incidence of first myocardial infarction or death from CHD.

Results  Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR], 0.14-0.71 vs 0.10-0.47; P<.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR, 1.30-2.75 vs 1.05-2.15; P<.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio (OR) for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% confidence interval [CI], 1.4-3.7; P for trend = .002) and 3.3 for IL-6 (95% CI, 2.0-5.5; P for trend <.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD ORs. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP.

Conclusions  These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.

Author Affiliations: Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine (Drs Pradhan, Manson, and Ridker) and Cardiology (Drs Pradhan and Ridker), and the Leducq Center for Molecular and Genetic Epidemiology of Cardiovascular Disorders (Dr Ridker), Brigham and Women's Hospital and Harvard Medical School, Boston, Mass; National Heart, Lung, and Blood Institute, Bethesda, Md (Dr Rossouw); Departments of Epidemiology and Medicine, University of Washington, Seattle (Dr Siscovick); Division of Community Geriatrics, Department of Family and Community Medicine, University of Texas Health Science Center, San Antonio (Dr Mouton); Department of Pathology, Children's Hospital Medical Center, and Harvard Medical School, Boston, Mass (Dr Rifai); Department of Epidemiology, University of Iowa College of Public Health, Iowa City (Dr Wallace); Division of Endocrinology, Diabetes, and Metabolism, Ohio State University, Columbus (Dr Jackson); and Women's Health Initiative Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, Wash (Ms Pettinger).

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