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Effects of conjugated equine estrogen in postmenopausal women with hysterectomy. The Women's Health Initiative Randomized Controlled Trial
Preventive Cardiology
tomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women. Perspective: This study of CEE was conducted in a high risk group, and is one of many high quality clinical trials demonstrating why placebo controlled trials are necessary prior to incorporating drug therapy into practice based simply on biologic plausibility or observational studies. However, the size of this study and the relatively low incremental risk (1.2 per 1000 patient-years) of strokes and very small (2 per 10,000 patient-years) excess risk of all events allows the woman and her physician to decide whether estrogen therapy targeting postmenopausal symptoms is worth it after weighing the knowledge regarding risk and benefits. MR
Abstracts Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy. The Women’s Health Initiative Randomized Controlled Trial The Women’s Health Initiative Steering Committee. JAMA 2004; 291:1701–12. Study Question: Does postmenopausal hormone replacement therapy reduce the prevalence of chronic diseases? Methods: A randomized, double-blind, placebo controlled disease prevention trial (the estrogen-alone component of the Women’s Health Initiative [WHI]) began in 1993 and enrolled 10,739 postmenopausal women, aged 50 –79 years with a prior hysterectomy. Women were randomly assigned to receive either 0.625 mg/day of conjugated equine estrogen (CEE) or placebo. Primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death), and invasive breast cancer incidence was the primary safety outcome. The summary overall effect was expressed via a global index of risks and benefits: primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture and deaths from other causes. Results: The mean age at entry was 63 years, 31% were 50 –59 years, and 25% were nonwhite. Age at the time of the hysterectomy was ⬍50 years in 82%, and 40% had undergone bilateral oophorectomy. About 52% had not used prior CEE. Body mass index averaged over 30kg/m2, and about 10% were current smokers, 15% had elevated cholesterol, nearly 50% had hypertension and 12% had CVD at baseline. In 2004, the National Institutes of Health ended the trial early. The incident number of cases and estimated hazard ratios (HRs) and 95% confidence interval for CEE vs. placebo for the major clinical outcomes at an average follow-up 6.8 years were: 376 CHD, 0.91 (0.75– 1.12); 218 breast cancer, 0.77 (0.59 –1.01); 276 strokes, 1.39 (1.10 –1.77); 85 PE, 1.34 (0.87–2.06); 119 colorectal cancers, 1.08 (0.75–1.55); and 102 hip fractures, 0.61 (0.41– 0.91). Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01–1.24); total cancer, 0.93 (0.81–1.07); total fractures, 0.70 (0.63– 0.79); total mortality, 1.04 (0.88 –1.22), and the global index, 1.01 (0.91–1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10,000 person-years and an absolute risk reduction of six fewer hip fractures per 10,000 personyears. The estimated excess risk for all monitored events in the global index was a nonsignificant two events per 10,000 person-years. Conclusions: The use of CEE increases the risk of stroke, decreases the risk of hip fracture and does not affect CHD incidence in postmenopausal women with prior hysterec-
A Walnut Diet Improves Endothelial Function in Hypercholesterolemic Subjects. A Randomized Crossover Trial Ros E, Nunez I, Perez-Heras A, et al. Circulation 2004;109;1609 – 14. Study Question: The Mediterranean diet provides a diet high in monounsaturated fat, particularly alpha linolenic acid, the plant source of 3 omega fatty acids, fiber, and antioxidants. Does replacing about 1⁄3 rd of the monounsaturated fats with walnut intake lower the cholesterol and improve brachial artery endothelial function in patients with hypercholesterolemia? Methods: The study was a randomized crossover design and included 21 hypercholesterolemic men and women comparing a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced ⬃32% of the energy from monounsaturated fat. Participants followed each diet for 4 weeks. Primary outcome was a comparison of the change in brachial artery flow mediated vasodilator response 4 hours after a lunch test meal of 550 – 650 kcal that varied by dietary fat source. Results: 8 men and 12 women who completed the trial had a mean age of 55 years (range 26 –75 years). Mean baseline LDL-C was 184 mg/dL, HDL-C 62 was mg/dL, triglycerides were 123 m/dL and apo B was 1.42 g/L. The walnut diet significantly reduced total cholesterol (⫺4.4⫾7.4%) and LDL-C (⫺6.4⫾10.0%), p⬍0.05 for both. Compared with the Mediterranean diet, the walnut diet improved endothelium-dependent vasodilation (increase from 3.4% to 45.9% or 64% compared to baseline) and reduced levels of VCAM-1 (p⬍0.05 for both). Endothelium-independent vasodilation and levels of ICAM-1, C-reactive protein, homocysteine and oxidation biomarkers were similar after each diet. Cholesterol, apo B and LDL-C reduction correlated with increases of both dietary ␣-linolenic acid and LDL ␥-tocopherol content (r⫽⬃⫺0.5, p⬍0.05 for each), and
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tomy over an average of 6.8 years. A possible reduction in breast cancer risk requires further investigation. The burden of incident disease events was equivalent in the CEE and placebo groups, indicating no overall benefit. Thus, CEE should not be recommended for chronic disease prevention in postmenopausal women. Perspective: This study of CEE was conducted in a high risk group, and is one of many high quality clinical trials demonstrating why placebo controlled trials are necessary prior to incorporating drug therapy into practice based simply on biologic plausibility or observational studies. However, the size of this study and the relatively low incremental risk (1.2 per 1000 patient-years) of strokes and very small (2 per 10,000 patient-years) excess risk of all events allows the woman and her physician to decide whether estrogen therapy targeting postmenopausal symptoms is worth it after weighing the knowledge regarding risk and benefits. MR
Abstracts Effects of Conjugated Equine Estrogen in Postmenopausal Women With Hysterectomy. The Women’s Health Initiative Randomized Controlled Trial The Women’s Health Initiative Steering Committee. JAMA 2004; 291:1701–12. Study Question: Does postmenopausal hormone replacement therapy reduce the prevalence of chronic diseases? Methods: A randomized, double-blind, placebo controlled disease prevention trial (the estrogen-alone component of the Women’s Health Initiative [WHI]) began in 1993 and enrolled 10,739 postmenopausal women, aged 50 –79 years with a prior hysterectomy. Women were randomly assigned to receive either 0.625 mg/day of conjugated equine estrogen (CEE) or placebo. Primary outcome was coronary heart disease (CHD) incidence (nonfatal myocardial infarction or CHD death), and invasive breast cancer incidence was the primary safety outcome. The summary overall effect was expressed via a global index of risks and benefits: primary outcomes plus stroke, pulmonary embolism (PE), colorectal cancer, hip fracture and deaths from other causes. Results: The mean age at entry was 63 years, 31% were 50 –59 years, and 25% were nonwhite. Age at the time of the hysterectomy was ⬍50 years in 82%, and 40% had undergone bilateral oophorectomy. About 52% had not used prior CEE. Body mass index averaged over 30kg/m2, and about 10% were current smokers, 15% had elevated cholesterol, nearly 50% had hypertension and 12% had CVD at baseline. In 2004, the National Institutes of Health ended the trial early. The incident number of cases and estimated hazard ratios (HRs) and 95% confidence interval for CEE vs. placebo for the major clinical outcomes at an average follow-up 6.8 years were: 376 CHD, 0.91 (0.75– 1.12); 218 breast cancer, 0.77 (0.59 –1.01); 276 strokes, 1.39 (1.10 –1.77); 85 PE, 1.34 (0.87–2.06); 119 colorectal cancers, 1.08 (0.75–1.55); and 102 hip fractures, 0.61 (0.41– 0.91). Corresponding results for composite outcomes were: total cardiovascular disease, 1.12 (1.01–1.24); total cancer, 0.93 (0.81–1.07); total fractures, 0.70 (0.63– 0.79); total mortality, 1.04 (0.88 –1.22), and the global index, 1.01 (0.91–1.12). For the outcomes significantly affected by CEE, there was an absolute excess risk of 12 additional strokes per 10,000 person-years and an absolute risk reduction of six fewer hip fractures per 10,000 personyears. The estimated excess risk for all monitored events in the global index was a nonsignificant two events per 10,000 person-years. Conclusions: The use of CEE increases the risk of stroke, decreases the risk of hip fracture and does not affect CHD incidence in postmenopausal women with prior hysterec-
A Walnut Diet Improves Endothelial Function in Hypercholesterolemic Subjects. A Randomized Crossover Trial Ros E, Nunez I, Perez-Heras A, et al. Circulation 2004;109;1609 – 14. Study Question: The Mediterranean diet provides a diet high in monounsaturated fat, particularly alpha linolenic acid, the plant source of 3 omega fatty acids, fiber, and antioxidants. Does replacing about 1⁄3 rd of the monounsaturated fats with walnut intake lower the cholesterol and improve brachial artery endothelial function in patients with hypercholesterolemia? Methods: The study was a randomized crossover design and included 21 hypercholesterolemic men and women comparing a cholesterol-lowering Mediterranean diet and a diet of similar energy and fat content in which walnuts replaced ⬃32% of the energy from monounsaturated fat. Participants followed each diet for 4 weeks. Primary outcome was a comparison of the change in brachial artery flow mediated vasodilator response 4 hours after a lunch test meal of 550 – 650 kcal that varied by dietary fat source. Results: 8 men and 12 women who completed the trial had a mean age of 55 years (range 26 –75 years). Mean baseline LDL-C was 184 mg/dL, HDL-C 62 was mg/dL, triglycerides were 123 m/dL and apo B was 1.42 g/L. The walnut diet significantly reduced total cholesterol (⫺4.4⫾7.4%) and LDL-C (⫺6.4⫾10.0%), p⬍0.05 for both. Compared with the Mediterranean diet, the walnut diet improved endothelium-dependent vasodilation (increase from 3.4% to 45.9% or 64% compared to baseline) and reduced levels of VCAM-1 (p⬍0.05 for both). Endothelium-independent vasodilation and levels of ICAM-1, C-reactive protein, homocysteine and oxidation biomarkers were similar after each diet. Cholesterol, apo B and LDL-C reduction correlated with increases of both dietary ␣-linolenic acid and LDL ␥-tocopherol content (r⫽⬃⫺0.5, p⬍0.05 for each), and
ACC CURRENT JOURNAL REVIEW Jun 2004
19