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제목 Effects of Hormone Replacement Therapy and Antioxidant Vitamin Supplements
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  • 작성일 2011-06-17
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  Vol. 288 No. 19, November 20, 2002 TABLE OF CONTENTS
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Effects of Hormone Replacement Therapy and Antioxidant Vitamin Supplements on Coronary Atherosclerosis in Postmenopausal Women

A Randomized Controlled Trial

David D. Waters, MD; Edwin L. Alderman, MD; Judith Hsia, MD; Barbara V. Howard, PhD; Frederick R. Cobb, MD; William J. Rogers, MD; Pamela Ouyang, MD; Paul Thompson, MD; Jean Claude Tardif, MD; Lyall Higginson, MD; Vera Bittner, MD; Michael Steffes, MD, PhD; David J. Gordon, MD, PhD; Michael Proschan, PhD; Naji Younes, PhD; Joel I. Verter, PhD

JAMA. 2002;288:2432-2440.

ABSTRACT


Context  Hormone replacement therapy (HRT) and antioxidant vitamins are widely used for secondary prevention in postmenopausal women with coronary disease, but no clinical trials have demonstrated benefit to support their use.

Objective  To determine whether HRT or antioxidant vitamin supplements, alone or in combination, influence the progression of coronary artery disease in postmenopausal women, as measured by serial quantitative coronary angiography.

Design, Setting, and Patients  The Women's Angiographic Vitamin and Estrogen (WAVE) Trial, a randomized, double-blind trial of 423 postmenopausal women with at least one 15% to 75% coronary stenosis at baseline coronary angiography. The trial was conducted from July 1997 to January 2002 in 7 clinical centers in the United States and Canada.

Interventions  Patients were randomly assigned in a 2 x 2 factorial design to receive either 0.625 mg/d of conjugated equine estrogen (plus 2.5 mg/d of medroxyprogesterone acetate for women who had not had a hysterectomy), or matching placebo, and 400 IU of vitamin E twice daily plus 500 mg of vitamin C twice daily, or placebo.

Main Outcome Measure  Annualized mean (SD) change in minimum lumen diameter (MLD) from baseline to concluding angiogram of all qualifying coronary lesions averaged for each patient. Patients with intercurrent death or myocardial infarction (MI) were imputed the worst rank of angiographic outcome.

Results  The mean (SD) interval between angiograms was 2.8 (0.9) years. Coronary progression, measured in mean (SD) change, worsened with HRT by 0.047 (0.15) mm/y and by 0.024 (0.15) mm/y with HRT placebo (P = .17); and for antioxidant vitamins by 0.044 (0.15) mm/y and with vitamin placebo by 0.028 (0.15) mm/y (P = .32). When patients with intercurrent death or MI were included, the primary outcome showed an increased risk for women in the active HRT group (P = .045), and suggested an increased risk in the active vitamin group (P = .09). Fourteen patients died in the HRT group and 8 in the HRT placebo group (hazard ratio [HR], 1.8; 95% confidence interval [CI], 0.75-4.3), and 16 in the vitamin group and 6 in the vitamin placebo group (HR, 2.8; 95% CI, 1.1-7.2). Death, nonfatal MI, or stroke occurred in 26 HRT patients vs 15 HRT controls (HR, 1.9; 95% CI, 0.97-3.6) and in 26 vitamin patients and 18 vitamin controls (HR, 1.5; 95% CI, 0.80-2.9). There was no interaction between the 2 treatment interventions.

Conclusion  In postmenopausal women with coronary disease, neither HRT nor antioxidant vitamin supplements provide cardiovascular benefit. Instead, a potential for harm was suggested with each treatment.



INTRODUCTION

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 • Introduction
 • Methods
 • Results
 • Comment
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 • References

In numerous observational studies over the past 30 years, postmenopausal estrogen replacement therapy, with or without a progestin, has been consistently associated with a reduced risk of coronary events, both in women with and without evidence of coronary disease.1-5 Estrogen exerts beneficial effects on blood lipids, low-density lipoprotein (LDL) oxidation, vascular function, and on some aspects of the coagulation system.6 Yet hormone replacement therapy (HRT) was not shown to be beneficial in the only 2 randomized, placebo-controlled trials of postmenopausal women with coronary disease.7-9 Furthermore, the only large primary prevention trial of HRT reported to date, the Women's Health Initiative, was stopped prematurely because overall risk exceeded benefit, including an increased risk of nonfatal myocardial infarction (MI) and coronary death, which was the study's primary outcome.10 As a result of this discrepancy between clinical trial results and other evidence, guidelines do not offer consistent, explicit recommendations for the use of this therapy in postmenopausal women.11

Like HRT, antioxidant consumption, either dietary or in the form of vitamin supplements, has been associated with a reduced risk of coronary disease in epidemiological studies.12-16 In a coronary angiographic trial, participants who took supplemental vitamin E (not as part of the trial) demonstrated less lesion progression.17 Theoretically, antioxidants inhibit a key component of atherogenesis (oxidation of LDL cholesterol within the vessel wall), and other mechanisms have been demonstrated in animal experiments, including preservation of nitric oxide activity, inhibition of leukocyte adhesion, reduction of cellular oxidative injury, and inhibition of platelet adhesion.18

Five randomized, placebo-controlled trials of vitamin E in patients with or at risk for coronary disease have been completed,19-23 and all but the smallest and shortest20 reported no benefit. Although the antioxidant effects of vitamins E and C may be synergistic, vitamin C was combined with vitamin E in only 1 of these trials.23 In addition to inhibiting LDL oxidation through a variety of mechanisms, vitamin C also exhibits other anti-atherosclerotic effects in animal models.24

To study possible benefits left unexplored by previous studies, the Women's Angiographic Vitamin and Estrogen (WAVE) Trial tested the combination of relatively high doses of vitamins E and C. Patients were randomized to HRT and/or antioxidant vitamins in a placebo-controlled 2 x 2 factorial design. The study population consisted of postmenopausal women with documented coronary disease, and the end point was the change in minimum lumen diameter (MLD) of qualifying coronary lesions.


METHODS

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 • Introduction
 • Methods
 • Results
 • Comment
 • Author information
 • References

Study Participants

Women were recruited between July 1997 and August 1999 at 7 clinical sites in the United States and Canada. The institutional review board at each site approved the study. The study design and methods have been reported previously.25 Women were eligible if they provided informed consent, were postmenopausal, and if a coronary angiogram performed within 4 months of study entry (according to the study protocol) demonstrated 1 or more 15% to 75% coronary stenoses in an artery not subjected to intervention. The protocol also specified that if the angiogram was performed within 2 weeks of an MI, the qualifying segment could not be related to the infarct. Baseline films were reviewed by the Angiographic Core Laboratory (Stanford University, Stanford, Calif) to confirm angiographic eligibility. Postmenopausal status was defined as having had a bilateral oophorectomy at any age, being younger than 55 years old with a follicle-stimulating hormone level of 40 mIU/mL or higher, or being older than 55 years.

Major exclusion criteria were HRT use within 3 months; concurrent use of more than 60 mg/d of vitamins C or 30 IU/d of E and unwillingness to stop taking them; evidence of potential breast, uterine, or cervical cancer; uncontrolled diabetes or hypertension; MI within 4 weeks; prior or planned coronary artery bypass graft surgery; fasting levels of triglycerides higher than 500 mg/dL (5.65 mmol/L); creatinine level higher than 2.0 mg/dL (176.8 µmol/L); symptomatic gallstones; New York Heart Association class IV heart failure or a left ventricular ejection fraction known to be less than 25%; history of hemorrhagic stroke, bleeding diathesis, pulmonary embolus, idiopathic deep vein thrombosis; or untreated osteoporosis.

Randomization and Treatment

After enrollment, women were randomly assigned to 4 treatment groups of equal size stratified by clinical center and previous hysterectomy status (14 strata), using a permuted block design with fixed block sizes of 4. Women received 400 IU of vitamin E and 500 mg of vitamin C, or an identical-appearing placebo to be taken twice daily, with or without HRT. Women with a prior hysterectomy took 1 tablet containing conjugated equine estrogens (0.625 mg of Premarin; Wyeth Pharmaceuticals, Collegeville, Pa) or an identical placebo tablet daily; women who had not had a hysterectomy took 1 tablet containing conjugated equine estrogens and medroxyprogesterone acetate (0.625 mg/2.5 mg of Prempro, Wyeth Pharmaceuticals) or an identical placebo tablet daily.

Participants, the investigators at the central biochemistry and angiography laboratories, and staff at the clinical centers (except the clinic gynecologist when necessary) were blinded to treatment assignments. To preserve complete blinding of clinic staff, breast and gynecologic symptoms were evaluated and managed by a separate gynecologic coordinator and study gynecologist.

Follow-up Procedures

All women were contacted by telephone 1 month after randomization and returned to the clinic for a follow-up visit at 3 months. Clinic visits thereafter were scheduled for 6-month intervals until the end of the trial. At each visit, symptoms were assessed, interim medical history ascertained, and adherence to medication checked by tablet/capsule counts. The following measurements and examinations were performed at baseline and every 12 months: height, weight, blood pressure level, waist circumference-to-hip ratio, pelvic examination, Papanicolaou test, mammography, and physical examination. Quality of life was measured and blood for central analysis obtained at baseline, 18 months, and at the end of the study. Endometrial biopsy, or if not possible, transvaginal ultrasound, was performed 6 months after baseline for women who developed any bleeding while taking the study medication. The clinic gynecologist interpreted the results and consulted with the patient.

Clinical events were systematically captured to monitor safety. At each visit, study nurses asked each woman about any hospitalization and reported events were recorded on a study data collection form. Appropriate documentation was obtained for all protocol clinical events. Based on standard criteria,9 4 members of the steering committee who were blinded to the treatment assignment classified all potential MIs and deaths.

Study exit angiograms were scheduled and obtained a mean (SD) of 2.8 (0.9) years after the initial study (January 2001 through January 2002). We attempted to perform both the baseline and follow-up angiograms under similar, optimal conditions. Coronary injections were to be performed after the administration of 0.4 mg of sublingual or intracoronary nitroglycerin using nonionic contrast media and a 6F catheter or larger, and all coronary arteries were visualized in a minimum of 2 standardized orthogonal projections. Intercurrent angiograms done for clinical indications were reviewed to determine whether revascularization had been performed. These films were used for angiographic end-point analysis in patients for whom an exit angiogram could not be obtained. Clinically indicated coronary angiograms performed within 6 months before the scheduled exit angiogram were counted as the exit angiogram and not repeated unless a subsequent coronary event occurred.

Of the 423 women enrolled, 306 underwent a follow-up angiogram and did not die or have a nonfatal MI. Twenty-two women died, 8 had a nonfatal MI, 74 had their scheduled exit visit but did not have an exit angiogram, and 13 were recorded as lost to follow-up prior to their scheduled exit visit. Of these 13, five were known to be alive between randomization and 1 year, 3 between 1 and 2 years, and 5 between 2 and 3 years. The distribution of patients within these categories per treatment group is listed in Figure 1. Clinical status at the scheduled exit visit was known for all but 3% of the study cohort. Of the 30 women who died or had a MI, 14 had an intercurrent film.



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Figure 1. Flow Diagram for WAVE Trial

Asterisk indicates most refused and some developed medical conditions that increased the risk of angiography. Dagger indicates the 30 women who died or experienced nonfatal myocardial infarction (MI) were assigned per protocol a worst score in the primary outcome analysis.


Among the women with angiographic follow-up, those assigned to HRT took 67% of their prescribed medication according to pill counts, and those assigned to HRT placebo took 70%. The corresponding figures were both 84% for antioxidant vitamins and vitamin placebo. Nine women assigned to placebo estrogen crossed over to open-label estrogen, and 1 woman assigned to placebo vitamin supplements crossed over to open-label vitamins.

Angiographic Measurements

Angiographic core laboratory staff were blinded to treatment assignment. Computer-assisted quantitation of stenosis and segment dimensions was performed on cine film recordings using custom modified 35-mm cine projectors with an integrated megapixel digitizing camera, as previously described.25-26 Angiograms recorded on CDs using the standard DICOM format provided direct digital imaging data. Angiographic images of individual lesions were selected from orthogonal views that best visualized the stenosis and that maximized the degree of stenosis for eccentric lesions. The factors influencing the choice of a specific frame were adequacy of vessel opacification, avoidance of vessel overlap, similarity of views between baseline and follow-up studies, and similar timing within the cardiac cycle.

For stenosis quantitation, the operator identified the lesion-containing segment length, the proximal and distal extent of the lesion, and the location of proximal and distal vessel diameter references, and outlined approximate vessel wall boundaries to facilitate computer quantitation. References were selected to be physiologically relevant to the lesion by identifying only those that are not separated from the stenosis by any substantial branch vessel. Dimensional calibration was based on contrast-filled catheter size as specified by the clinical sites. The quantitation program determined final vessel boundaries based on first and second derivative–edge-finding algorithms from which the MLD, mean lumen diameter, and percentage stenosis (based on available reference diameters) were computed. When remeasured by the same technician, the mean (SD) change in MLD was -0.004 (0.22) mm; when remeasured by a different technician, the change was 0.005 (0.081) mm.

Statistical Analyses

The sample size calculation, as previously described,25 was based on the results of previous coronary angiographic trials that evaluated cholesterol-lowering therapy. Our sample size of 423 women would provide a power of approximately 90% to detect an effect size of at least 0.33 (corresponding to a change in MLD of approximately 0.1 mm), using a 2-tailed test and assuming that 20% of the women would not undergo a follow-up angiogram. The primary study end point (identified at the beginning of the trial) is based on change in the mean MLD of all qualifying segments of WAVE participants, and on the incidence of MI and death. Angiographic progression and clinical events analyzed separately were identified as secondary end points. WAVE qualifying segments were defined as segments with 15% to 75% stenoses at baseline or new lesions at follow-up. The annualized mean change in the MLD from baseline to concluding angiogram (or to intercurrent angiogram prior to revascularization) was calculated for all available WAVE qualifying lesions and averaged for each patient. The primary end point in the treated and control group was compared using a nonparametric rank test based on the Van der Waerden scores.27 Patients with intercurrent death or MI were assigned the worst ranks. All analyses were intention-to-treat. For those participants who did not undergo follow-up angiography and did not die or have an MI, baseline angiography was carried forward for analysis and change over time was zero. Intergroup comparisons of baseline features and clinical outcomes were done using t tests, {chi}2 tests, or Fisher exact tests as appropriate. Adjusted analyses of the primary end point were performed by least squares regression of the Van der Waerden scores against a treatment indicator and other appropriate covariates. Statistical analyses were performed using SAS statistical software (Version 8, SAS institute Inc, Cary, NC). All tests were 2-sided with {alpha} = .05.


RESULTS

 Jump to Section
 • Top
 • Introduction
 • Methods
 • Results
 • Comment
 • Author information
 • References

Baseline Characteristics

The baseline features of the study population are summarized in Table 1. The mean age was 65 years and one third of the women were nonwhite (predominantly black). More than one third of the patients were diagnosed as having diabetes, and the mean fasting blood glucose level for the entire group was 126 mg/dL (7 mmol/L). The mean body mass index of the women was high (30.7), as was the average level of fasting serum triglycerides (162 mg/dL; 1.83 mmol/L). Although nearly 60% of the women were being treated with cholesterol-lowering drugs, the mean LDL cholesterol level was 118 mg/dL (3.06 mmol/L), which is higher than the level recommended for patients with coronary disease.


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