- Email: [email protected]
progestin combinations, and nonusers
Comparison of Angiographic Findings Among Postmenopausal Women Using Unopposed Estrogen, Estrogen/Progestin Combinations, and Nonusers Liudmila Husak, MD, MPH, Viola Vaccarino, MD, PhD, Emir Veledar, Nancy Murrah, RN, BSN, and Nanette K. Wenger, MD
PhD,
Studies of the effects of menopausal hormone therapy on coronary artery disease (CAD) in postmenopausal women have provided contradictory results. Although recent experimental studies have revealed no beneficial effect of combination therapy with estrogen (E) and progesterone (P), the effect of monotherapy with E remains unknown. We retrospectively examined the medical records of 843 consecutive women aged >55 years who underwent their first cardiac catheterization between January 1996 and December 1998. We compared the presence and severity of CAD, defined as >1 diseased coronary vessel (with stenosis >50%), in women who only took E, EⴙP, or no menopausal hormone therapy. In all, 210 women (33%) took hormones, of whom 47 (22%) used EⴙP and 163 (78%) used E only. Women who used any hormones tended to be healthier than nonusers, but EⴙP users had a lower prevalence of risk factors and co-morbidities than E users. In unad-
justed analyses, both the E and EⴙP groups were significantly less likely to have CAD than nonusers (relative risk [RR] 0.71, 95% confidence interval [CI] 0.58 to 0.84 for the E group; RR 0.76, 95% CI 0.54 to 0.99 for the EⴙP group). Demographic factors, CAD risk factors, comorbidities, and primary prevention medication use explained the association between EⴙP and the presence of CAD (RR 1.14, 95% CI 0.74 to 1.39). In contrast, adjustment for these factors had a minimal effect on the association between E and CAD compared with nonusers (RR 0.79, 95% CI 0.59 to 0.98). Thus, the apparent protective effect of combination menopausal hormone therapy with EⴙP on CAD is due to differences in other patient characteristics. In contrast, unopposed E therapy may have a protective effect on CAD. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:563–568)
everal observational and animal experimental studies suggest that progesterone (P) may attenuS ate a beneficial effect of estrogen (E) on the cardio-
E⫹P, is associated with less prevalent and less extensive CAD among women undergoing their first coronary angiography.
vascular system.1–11 Recent clinical trials of postmenopausal hormone therapy, such as the Women’s Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS), have indicated that the risk associated with E⫹P therapy outweighs the benefits.12,13 However, the HERS did not have an unopposed E arm. The unopposed E arm of the WHI trial among women who have had hysterectomies is ongoing. Therefore, it is not known whether postmenopausal treatment with E alone or E⫹P combinations differ in their effects on coronary atherosclerosis and coronary heart disease risk. The purpose of our study was to examine whether there are significant differences in coronary artery disease (CAD) prevalence and CAD severity between E and E⫹P users. We hypothesize that use of E, but not From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, and the Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia. This study was supported by Solvay, Pharmaceuticals, Inc., Marietta, Georgia. Dr. Husak was supported in part by the Edmund S. Muskie/Freedom Support Act Graduate Fellowship Program, New York, New York. Manuscript received July 17, 2003; revised manuscript received and accepted November 3, 2003. Address for reprints: Viola Vaccarino, MD, PhD, Emory University School of Medicine, 1256 Briarcliff Road, Suite 1, North, Atlanta, Georgia 30306. E-mail: [email protected]. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 March 1, 2004
METHODS
Patient population and data collection: We retrospectively examined the medical records of women aged ⱖ55 years who underwent their first cardiac catheterization at 2 major hospitals affiliated with the Emory University School of Medicine: Emory University Hospital and Crawford Long Hospital, Atlanta, Georgia. Data were abstracted from medical records and in part were obtained from an ongoing database, the Emory Main Cardiology Database. This project was approved by the Emory University Institutional Review Board. Our study included only women admitted for their first coronary angiography between January 1996 and June 1998. We determined this inclusion criterion to avoid the potential influence of prescription pattern changes caused by the release of the HERS findings in August 1998. To reflect a population of postmenopausal women, women aged ⬍55 years were excluded. In addition, to address the effect of E or E⫹P in the primary prevention of CAD, we also excluded women who had previously had cardiac catheterization with or without revascularization procedures. Demographic data (age and race), coronary heart 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.11.019
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disease risk factors (body mass index, family history of coronary heart disease, hyperlipidemia, and smoking), history of co-morbidities (diabetes, renal insufficiency, stroke, peripherial vascular disease surgery, and congestive heart failure), primary and secondary prevention medications (aspirin and lipid-lowering drugs), clinical characteristics (left ventricular ejection fraction, systolic and diastolic blood pressure), and data on menopausal hormone therapy use were obtained from admission histories, nursing records, and physician records. The accuracy of recording the type of hormonal therapy (E or E⫹P) in the medical records was verified by checking the presence of a history of hysterectomy in a random sample of 25 charts, and was found to be accurate. Data on degree of stenosis, number of diseased vessels, and left ventricular ejection fraction were abstracted from standardized coronary angiographic reports used in participating hospitals. The presence of CAD was defined as ⱖ50% stenosis in ⱖ1 vessel. Severity of CAD was quantified as the number of diseased vessels in 4 categories (none, 1, 2, or 3 vessels with ⱖ50% stenosis). Statistical analyses: Statistical comparisons of CAD severity, sociodemographic and clinical characteristics of nonusers, users of E, and users of E⫹P were conducted by means of a chi-square test for categorical variables and 1-way analysis of variance for continuous variables. Indicator variables were created for E and E⫹P use, with nonusers being the referent category. In a secondary analysis, the referent category was changed to E, which was used to address the differences in outcomes between E and E⫹P users. Sequential logistic regression models were used to calculate adjusted odds ratios [OR] for presence of CAD as a binary outcome after controlling for sociodemographic factors, co-morbidities, behavioral risk factors, and clinical symptoms. Because the OR tends to overestimate the relative risk (RR) when the outcome is frequent, we transformed the OR estimates to RR.14 Variables retained in the models were those that were clinically meaningful, statistically significant, and/or those that caused a change in the OR for CAD to ⬎10%. To assess the influence of menopausal hormone therapy on the severity of CAD, quantified as an increasing number of diseased vessels from none to 3, we used ordinal logistic regression models. Results from these latter models are presented as the OR. The level of statistical significance was set at 0.05 (2-sided for all tests). SAS Software, version 8.2 (SAS Inc., Cary, North Carolina) was used for the analyses.
RESULTS
Study sample: A total of 871 women satisfied the eligibility criteria. Complete covariable data on 7 patients could not be obtained due to missing information in the medical records. We also excluded 21 patients who underwent coronary angiography for non-CAD reasons or did not have information on the number of diseased vessels. Our final sample included 843 patients. Collection of information on aspirin and statin use in the Emory Main Cardiology Database
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began at a later date after the inception of the database. Therefore, this information is only available for a subset of patients (n ⫽ 484). Hormone therapy and prevalence of CAD: Of the 843 patients, 210 (33%) took hormones. Of those, 163 (77%) used E and 47 (22%) used E⫹P (Table 1). Hormone users were significantly younger and less often had a history of diabetes and renal insufficiency. Body mass index was essentially the same in the 3 groups. Hormone users were, overall, healthier than nonusers (Table 1). However, there were no significant differences in health status and prevalence of risk factors between E and E⫹P users, although E users tended to have a higher prevalence of CAD risk factors and co-morbidities (Table 1). In unadjusted analyses, E and E⫹P users had a significantly lower likelihood of CAD than nonusers. For E users, the RR of CAD was 0.71 (95% confidence interval [CI] 0.58 to 0.84) compared with nonusers, and in E⫹P users, the corresponding RR was 0.76 (95% CI 0.54 to 0.99) (Table 2). After adjustment for age, race, family history of coronary heart disease, body mass index, smoking history, hyperlipidemia, ejection fraction, congestive heart failure, cerebrovascular accident, renal insufficiency, and diabetes, E users continued to have a significantly lower risk of CAD than nonusers (RR 0.77, 95% CI 0.69 to 0.94). However, adjustment for the same covariables considerably weakened the association between E⫹P use and CAD prevalence, yielding an RR of 0.89, with a 95% CI from 0.59 to 1.16 (Table 2). The difference in results when comparing E or E⫹P users with nonusers became even more pronounced after adjustment for aspirin and statin use (E group: RR 0.79, 95% CI 0.59 to 0.98; E⫹P group: RR 1.14; 95% CI 0.74 to 1.39) (Table 2). When the analyses were repeated with E users as a referent category, E⫹P users had a significantly higher prevalence of CAD than E users after adjustment for all the same covariables and medication use (RR 1.31, 95% CI 1.03 to 1.46) (Table 2). Hormone therapy and severity of CAD: When we examined the association of hormone use with severity of CAD, the results were consistent with those for CAD prevalence. The unadjusted OR for the E group versus nonusers, with the number of diseased vessels as an ordinal dependent variable, was 0.47 (95% CI 0.34 to 0.65) (Table 3). Similarly, for E⫹P users, the unadjusted OR was 0.50 (95% CI 0.29 to 0.87) relative to nonusers (Table 3). These data indicate an approximate 50% increase in the odds of having a higher number of diseased vessels (from none to 1, or from 1 to 2, or from 2 to 3 vessels) when comparing either group of hormone users with nonusers. After adjusting for a similar set of covariables as in the previous analysis, the association in the E⫹P group was noticeably attenuated and no longer significant (OR 0.75, 95% CI 0.37 to 1.52) (Table 3), whereas E remained inversely related to severity of CAD (OR 0.61, 95% CI 0.40 to 0.92) (Table 3). Similar to the prevalence analyses, the divergence between E and E⫹P results was intensified after adjusting for aspirin and statin use (E users: OR 0.55, MARCH 1, 2004
TABLE 1 Characteristics of Study Population Postmenopausal Hormones Risk Factors Age, mean ⫾ SD (yrs) Body mass index (mean ⫾ SD) (kg/m2) Caucasian* Smoking history Current smoker Past smoker Never smoked Hyperlipidemia Myocardial infarction† None Acute or recent Remote Diabetes mellitus Cerebrovascular accident Renal insufficiency‡ Chronic heart failure, NYHA class 0 I II III IV Left ventricular ejection fraction (mean ⫾ SD) (%)§ Systolic blood pressure, (mean ⫾ SD) (mm Hg) Aspirin use㛳 Statins use㛳 No. of narrowed coronary arteries 0 1 2 3
p Value
Nonusers (n ⫽ 633)
E (n ⫽ 163)
E⫹P (n ⫽ 47)
E vs Nonusers
E⫹P vs Nonusers
E⫹P vs E
70 ⫾ 9 28 ⫾ 6 77%
66 ⫾ 7 28 ⫾ 6 89%
65 ⫾ 7 28 ⫾ 6 95%
⬍0.0001 0.81 0.0012 0.22
⬍0.0001 0.46 0.0065 0.35
0.57 0.55 0.37 0.59
15% 27% 58% 54%
14% 34% 53% 60%
19% 34% 47% 63%
0.20 0.10
0.25 0.08
0.70 0.55
66% 23% 11% 30% 9.79% 6.98%
74% 17% 8.59% 14% 5.52% 2.45%
81% 11% 8.51% 6% 2.13% 2.13%
⬍0.0001 0.09 0.03 0.03
0.0004 0.08 0.36 0.24
0.13 0.34 0.89 0.88
72% 3.32% 7.90% 9.00% 7.90% 53 ⫾ 14 140 ⫾ 24 61% 16%
84% 1.84% 4.29% 6.13% 3.68% 55 ⫾ 12 136 ⫾ 23 66% 23%
87% 2.13% 4.26% 2.13% 4.26% 55 ⫾ 12 141 ⫾ 23 62% 19%
0.07 0.03 0.39 0.09 ⬍0.0001
0.36 0.93 0.95 0.70 0.08
0.89 0.21 0.72 0.69 0.70
52% 21% 17% 9.82%
47% 30% 15% 8.51%
32% 28% 19% 21%
*There are 568 patients in the no-hormones group, 144 in the E group and 41 in the E⫹P group. † There are 631 patient in the no-hormone group. ‡ There are 630 patient in the no-hormone group. § There are 604 patients in the no-hormone group, 158 in the E group and 44 in the E⫹P group. 㛳 There are 484 patients in the no-hormone group, 118 in the E group and 26 in the E⫹P group. NYHA ⫽ New York Heart Association.
TABLE 2 Multivariable Analysis of Association Between Hormone Use and Presence of Coronary Artery Disease (CAD) RR (95% CI) for ⱖ1 Diseased Vessels Risk Factors Unadjusted Adjusted for demographic factors, comorbidities, and CAD risk factors*† Adjusted for all of the above and medications (aspirin and statins)‡
E vs. Nonusers
E⫹P vs Nonusers
E⫹P vs E
0.71 (0.58–0.84) 0.77 (0.60–0.94) 0.79 (0.59–0.98)
0.76 (0.54–0.99) 0.92 (0.61–1.20) 1.14 (0.74–1.39)
1.07 (0.83–1.26) 1.15 (0.89–1.34) 1.31 (1.03–1.46)
*Age, race, family history, body mass index, smoking, hyperlipidemia, diabetes, congestive heart failure, history of stroke, history of renal insufficiency, blood pressure, ejection fraction. † There were 767 observations. ‡ There were 576 observations.
95% CI 0.32 to 0.94; E⫹P users: OR 1.51, 95% CI 0.51 to 4.45) (Table 3). In analyses with E users as a referent group, a pattern of more severe CAD in E⫹P users than in E users was also observed (Table 3). In all these models, the score test for the proportional odds assumption was satisfied, indicating that the ordinal logistic model was appropriate.
DISCUSSION Our results indicate that E users have less prevalent and less severe CAD than nonusers, but E⫹P users
have CAD similar to nonusers. Consistent with other observational studies, hormone users in our study were healthier and had a more favorable coronary heart disease risk profile than nonusers.15–17 In unadjusted analyses, both groups of hormone users (E and E⫹P) had a significantly lower likelihood of CAD. However, in adjusted analyses, the apparent protective effect of combination hormone therapy was explained by other covariables, e.g., E⫹P users were younger, had fewer co-morbidities and coronary heart disease risk factors, and tended to take primary prevention
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565
TABLE 3 Multivariable Analysis of Association Between Severity of Coronary Artery Disease (CAD) and Hormone Use OR (95% CI) for Higher Number of Diseased Vessels Risk Factors Unadjusted Adjusted for demographic factors, comorbidities, and CAD risk factors*† Adjusted for all of the above and medications (aspirin and statins)‡
E vs Nonusers
E⫹P vs Nonusers
E⫹P vs E
0.47 (0.34–0.65) 0.61 (0.40–0.92) 0.55 (0.32–0.94)
0.50 (0.29–0.87) 0.75 (0.37–1.52) 1.51 (0.51–4.45)
1.07 (0.58–1.95) 1.28 (0.66–2.45) 2.06 (0.91–4.66)
*Age, race, family history, body mass index, smoking, hyperlipidemia, diabetes, congestive heart failure, history of stroke, history of renal insufficiency, blood pressure, ejection fraction. † There were 767 observations. ‡ There were 576 observations.
medications more often than nonusers. In contrast, use of unopposed E remained significantly associated with less CAD. Results were similar when the number of diseased vessels was examined as a measure of CAD severity, as opposed to a dichotomous CAD variable. Although the adjusted odds for more severe CAD comparing E⫹P users with nonusers were 51% higher, those comparing E users with nonusers were 45% lower. By directly comparing E⫹P with E users, we found that E⫹P users had a higher CAD prevalence and severity than E users. It is unlikely that the protective effect of E is due to residual confounding or unmeasured factors for the following reasons. First, the E group had an overall higher risk profile than the E⫹P group; therefore, if residual confounding existed, it should have affected the E group more than the E⫹P group. This would result in a smaller benefit of E use, i.e., higher odds of CAD in E users than in E⫹P users. Second, although we did not have measures of socioeconomic status, there is reason to believe that the E and E⫹P groups should be fairly comparable in terms of education and other socioeconomic status characteristics. Few observational studies of menopausal hormone therapy have provided separate data on the effect of either E alone or E⫹P on CAD end points.18 –20 Consistent with our results, data on unopposed E therapy mostly points toward a significant reduction in CAD progression.21,22 In a recent meta-analysis by Humphrey et al,23 no risk reduction in CAD was observed in either E or E⫹P users after adjustment for socioeconomic status and other contributing factors. This study again did not examine E and E⫹P use separately. Of the secondary prevention trials of menopausal hormone therapy in women with established CAD, only 3 have presented data on unopposed E. The EStrogen in the Prevention of ReInfarction Trial (ESPRIT) examined the role of estradiol in the prevention of subsequent cardiac events in 1,017 women who survived their first myocardial infarction. In this trial, estradiol did not reduce the risk of further cardiac events.24 Similarly, the Estrogen Replacement and Atherosclerosis (ERA) trial found no effect of either E or E⫹P on the progression of coronary atherosclerosis as measured by serial coronary angiography.25 Another angiographic secondary prevention trial, the Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL566 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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HART), found no reduction in coronary lesions in 226 postmenopausal women with ⱖ1 diseased coronary vessel who received either E or E⫹P compared with those taking placebos.26 Of the published primary prevention trials, the most relevant trials for our population, the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) is the only trial that provided data on unopposed E for primary prevention. This was a randomized, doubleblind controlled trial of the effect of 17-estradiol on carotid artery intima-media thickness in 222 asymptomatic postmenopausal women.27 This trial found a significant reduction in the progression of atherosclerosis among estradiol users, but only in the absence of concomitant statin use. A similar randomized controlled trial, Postmenopausal HOrmone REplacement against Atherosclerosis (PHOREA), found no benefit of a combined hormone regimen toward reducing the progression of carotid intima-media thickness in women with increased carotid artery intima-media thickness at baseline.28 However, this trial did not have an E-only arm. Finally, the WHI E/progestin study of 16,608 healthy postmenopausal women found no benefits from this combination hormone regimen, but observed an excess coronary and stroke risk.13 The E-only arm of WHI, however, is still ongoing; therefore, results pertaining to unopposed E therapy in this trial are not known (Table 4). Study limitations: The number of E⫹P users was relatively small. It is unlikely that this affected our conclusions, because the estimate for the comparison of E⫹P users with nonusers was ⬎1 after multivariable analysis, whereas the estimate for E users remained well below 1. We did not have data on the different types of E (transdermal vs oral) or progestin (micronized P vs medroxyprogesterone acetate) that were used by these patients. We also cannot demonstrate temporality of association between menopausal hormone therapy use and CAD and determine the time frame of hormone use with respect to the angiography in the 2 groups of users. Another limitation is that the assessment of CAD in our study was based on visual interpretation of the lesion severity, because quantitative coronary angiographic analysis was not available. However, there is no reason to believe that visual interpretation should be biased on the basis of the hormone use, because it is unlikely that radiologists were aware of the patients’ hormonal status. Finally, our study population was composed of women reMARCH 1, 2004
⻫
⻫
⻫
⻫ ⻫
PHOREA ESPRIT ERA WAVE HERS WELLHART
See text for explanation of trial abbreviations. CEE ⫽ conjugated equine estrogen; IMT ⫽ intima-media thickness; MPA ⫽ medroxyprogesterone acetate.
⻫
⻫
17 Estradiol ⫹ gestodine 17 Estradiol CEE, CEE ⫹ MPA CEE, CEE ⫹ MPA but no between-groups comparison CEE ⫹ MPA 17 Estradiol, 17 estradiol ⫹ MPA ⻫ ⻫ ⻫ ⻫ ⻫
Secondary Prevention Trials
⻫ CEE, CEE ⫹ MPA 17 Estradiol
Primary Prevention Trials
⻫ ⻫ ⻫ ⻫ WHI EPAT
Trial
0 0 0 0 0 0
?/0 ⫹
Benefit Comparison Between Hormone Regimens (E vs EP) Tested Type of Hormone Regimen(s) Studied Unopposed Estrogen Tested Coronary Heart Disease Events End Points
Carotid IMT Coronary Angiography
TABLE 4 Comparison of Randomized Clinical Trials
ferred for coronary angiography; therefore, our study may not be generalizable to all women. Because we are dealing with a referral population, the possibility of different thresholds of referral and evaluation between hormone users and nonusers cannot be excluded. Despite these limitations, this is the first study addressing this question in a large sample of women with objective assessment of CAD. Conclusions: Our results suggest that the addition of P in treatment therapies may attenuate a potentially beneficial effect of unopposed E toward coronary heart disease risk. Further experimental studies are required to investigate whether the apparent angiographic benefit of E monotherapy observed in this study is truly due to E therapy, and whether this association results in an actual reduction of coronary heart disease events. Until this evidence is obtained, women should be discouraged from using any hormone regimens for the sole purpose of coronary heart disease prevention.29 1. Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 2002;23:665–686. 2. Gerhard M, Walsh BW, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy combined with progesterone and endotheliumdependent vasodilation in postmenopausal women. Circulation 1998;98:1158 – 1163. 3. Godsland IF. Hormone replacement therapy and carbohydrate metabolism in cardiovascular risk. In: Lobo RA, ed. Treatment of the Postmenopausal Women: Basic and Clinical Aspects. Philadelphia: Lippincott Williams & Wilkins, 1999: 391–395. 4. Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E. Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. The Menopause Study Group. Obstet Gynecol 1994;84:987–995. 5. Mercuro G, Pitzalis L, Podda A, Zoncu S, Pilia I, Melis GB, Cherchi A. Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women. Am J Cardiol 1999;84:214 –218. 6. Rosano GM, Sarais C, Zoncu S, Mercuro G. The relative effects of progesterone and progestins in hormone replacement therapy. Hum Reprod 2000;15: 60 –73. 7. Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17estradiol and norethisterone acetate: a two-year follow-up study. Hypertension 1995;25:848 –853. 8. Sullivan JM, Shala BA, Miller LA, Lerner JL, McBrayer JD. Progestin enhances vasoconstrictor responses in postmenopausal women receiving estrogen replacement therapy. Menopause 1995;2:193–199. 9. Vogel RA, Corretti MC. Estrogens, progestins, and heart disease: can endothelial function divine the benefit? Circulation 1998;97:1223–1226. 10. Walsh B, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks F. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196 –1204. 11. Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757–1761. 12. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49 –57. 13. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. 14. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690 –1691. 15. Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 1996;143:971–978. 16. Humphrey LL, Nelson HD, Chan BK, Nygren P, Allan J, Teutsch S. Relationship between hormone replacement therapy, socioeconomic status, and coronary heart disease. JAMA 2003;289:45–46. 17. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002;288:872– 881.
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18. Hong MK, Romm PA, Reagan K, Green CE, Rackley CE. Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. Am J Cardiol 1992;69:176 –178. 19. McFarland KF, Boniface ME, Hornung CA, Earnhardt W, Humphries JO. Risk factors and noncontraceptive estrogen use in women with and without coronary disease. Am Heart J 1989;117:1209 –1214. 20. Sullivan JM, Vander Zwaag R, Lemp GF, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, Mirvis DM. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med 1988;108:358 –363. 21. Falkeborn M, Persson I, Adami HO, Bergstrom R, Eaker E, Lithell H, Mohsen R, Naessen T. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 1992;99:821–828. 22. Grodstein FS, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933– 941. 23. Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137:273–289. 24. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M, Buckley H, The ET. Oestrogen therapy
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for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002;360:2001–2008. 25. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–529. 26. Hodis HN, Mack WJ, Azen SP, Lobo RA, Shoupe D, Mahrer PR, Faxon DP, Cashin-Hemphill L, Sanmarco ME, French WJ, et al. Hormone therapy and the progression of coronary artery atherosclerosis in postmenopausal women. N Engl J Med 2003;349:535–545. 27. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu CR, Liu CH, Azen SP. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135: 939 –953. 28. Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262–268. 29. FDA. The estrogen and progestin dilemma: new advice, and labeling guidelines. Available at: http://www.fda.gov/fdac/features/2003/203_estrogen.html. Accessed on Jan. 15, 2004.
MARCH 1, 2004
PhD,
Studies of the effects of menopausal hormone therapy on coronary artery disease (CAD) in postmenopausal women have provided contradictory results. Although recent experimental studies have revealed no beneficial effect of combination therapy with estrogen (E) and progesterone (P), the effect of monotherapy with E remains unknown. We retrospectively examined the medical records of 843 consecutive women aged >55 years who underwent their first cardiac catheterization between January 1996 and December 1998. We compared the presence and severity of CAD, defined as >1 diseased coronary vessel (with stenosis >50%), in women who only took E, EⴙP, or no menopausal hormone therapy. In all, 210 women (33%) took hormones, of whom 47 (22%) used EⴙP and 163 (78%) used E only. Women who used any hormones tended to be healthier than nonusers, but EⴙP users had a lower prevalence of risk factors and co-morbidities than E users. In unad-
justed analyses, both the E and EⴙP groups were significantly less likely to have CAD than nonusers (relative risk [RR] 0.71, 95% confidence interval [CI] 0.58 to 0.84 for the E group; RR 0.76, 95% CI 0.54 to 0.99 for the EⴙP group). Demographic factors, CAD risk factors, comorbidities, and primary prevention medication use explained the association between EⴙP and the presence of CAD (RR 1.14, 95% CI 0.74 to 1.39). In contrast, adjustment for these factors had a minimal effect on the association between E and CAD compared with nonusers (RR 0.79, 95% CI 0.59 to 0.98). Thus, the apparent protective effect of combination menopausal hormone therapy with EⴙP on CAD is due to differences in other patient characteristics. In contrast, unopposed E therapy may have a protective effect on CAD. 䊚2004 by Excerpta Medica, Inc. (Am J Cardiol 2004;93:563–568)
everal observational and animal experimental studies suggest that progesterone (P) may attenuS ate a beneficial effect of estrogen (E) on the cardio-
E⫹P, is associated with less prevalent and less extensive CAD among women undergoing their first coronary angiography.
vascular system.1–11 Recent clinical trials of postmenopausal hormone therapy, such as the Women’s Health Initiative (WHI) trial and the Heart and Estrogen/progestin Replacement Study (HERS), have indicated that the risk associated with E⫹P therapy outweighs the benefits.12,13 However, the HERS did not have an unopposed E arm. The unopposed E arm of the WHI trial among women who have had hysterectomies is ongoing. Therefore, it is not known whether postmenopausal treatment with E alone or E⫹P combinations differ in their effects on coronary atherosclerosis and coronary heart disease risk. The purpose of our study was to examine whether there are significant differences in coronary artery disease (CAD) prevalence and CAD severity between E and E⫹P users. We hypothesize that use of E, but not From the Department of Medicine, Division of Cardiology, Emory University School of Medicine, Atlanta, and the Department of Epidemiology, Rollins School of Public Health, Atlanta, Georgia. This study was supported by Solvay, Pharmaceuticals, Inc., Marietta, Georgia. Dr. Husak was supported in part by the Edmund S. Muskie/Freedom Support Act Graduate Fellowship Program, New York, New York. Manuscript received July 17, 2003; revised manuscript received and accepted November 3, 2003. Address for reprints: Viola Vaccarino, MD, PhD, Emory University School of Medicine, 1256 Briarcliff Road, Suite 1, North, Atlanta, Georgia 30306. E-mail: [email protected]. ©2004 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 93 March 1, 2004
METHODS
Patient population and data collection: We retrospectively examined the medical records of women aged ⱖ55 years who underwent their first cardiac catheterization at 2 major hospitals affiliated with the Emory University School of Medicine: Emory University Hospital and Crawford Long Hospital, Atlanta, Georgia. Data were abstracted from medical records and in part were obtained from an ongoing database, the Emory Main Cardiology Database. This project was approved by the Emory University Institutional Review Board. Our study included only women admitted for their first coronary angiography between January 1996 and June 1998. We determined this inclusion criterion to avoid the potential influence of prescription pattern changes caused by the release of the HERS findings in August 1998. To reflect a population of postmenopausal women, women aged ⬍55 years were excluded. In addition, to address the effect of E or E⫹P in the primary prevention of CAD, we also excluded women who had previously had cardiac catheterization with or without revascularization procedures. Demographic data (age and race), coronary heart 0002-9149/04/$–see front matter doi:10.1016/j.amjcard.2003.11.019
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disease risk factors (body mass index, family history of coronary heart disease, hyperlipidemia, and smoking), history of co-morbidities (diabetes, renal insufficiency, stroke, peripherial vascular disease surgery, and congestive heart failure), primary and secondary prevention medications (aspirin and lipid-lowering drugs), clinical characteristics (left ventricular ejection fraction, systolic and diastolic blood pressure), and data on menopausal hormone therapy use were obtained from admission histories, nursing records, and physician records. The accuracy of recording the type of hormonal therapy (E or E⫹P) in the medical records was verified by checking the presence of a history of hysterectomy in a random sample of 25 charts, and was found to be accurate. Data on degree of stenosis, number of diseased vessels, and left ventricular ejection fraction were abstracted from standardized coronary angiographic reports used in participating hospitals. The presence of CAD was defined as ⱖ50% stenosis in ⱖ1 vessel. Severity of CAD was quantified as the number of diseased vessels in 4 categories (none, 1, 2, or 3 vessels with ⱖ50% stenosis). Statistical analyses: Statistical comparisons of CAD severity, sociodemographic and clinical characteristics of nonusers, users of E, and users of E⫹P were conducted by means of a chi-square test for categorical variables and 1-way analysis of variance for continuous variables. Indicator variables were created for E and E⫹P use, with nonusers being the referent category. In a secondary analysis, the referent category was changed to E, which was used to address the differences in outcomes between E and E⫹P users. Sequential logistic regression models were used to calculate adjusted odds ratios [OR] for presence of CAD as a binary outcome after controlling for sociodemographic factors, co-morbidities, behavioral risk factors, and clinical symptoms. Because the OR tends to overestimate the relative risk (RR) when the outcome is frequent, we transformed the OR estimates to RR.14 Variables retained in the models were those that were clinically meaningful, statistically significant, and/or those that caused a change in the OR for CAD to ⬎10%. To assess the influence of menopausal hormone therapy on the severity of CAD, quantified as an increasing number of diseased vessels from none to 3, we used ordinal logistic regression models. Results from these latter models are presented as the OR. The level of statistical significance was set at 0.05 (2-sided for all tests). SAS Software, version 8.2 (SAS Inc., Cary, North Carolina) was used for the analyses.
RESULTS
Study sample: A total of 871 women satisfied the eligibility criteria. Complete covariable data on 7 patients could not be obtained due to missing information in the medical records. We also excluded 21 patients who underwent coronary angiography for non-CAD reasons or did not have information on the number of diseased vessels. Our final sample included 843 patients. Collection of information on aspirin and statin use in the Emory Main Cardiology Database
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began at a later date after the inception of the database. Therefore, this information is only available for a subset of patients (n ⫽ 484). Hormone therapy and prevalence of CAD: Of the 843 patients, 210 (33%) took hormones. Of those, 163 (77%) used E and 47 (22%) used E⫹P (Table 1). Hormone users were significantly younger and less often had a history of diabetes and renal insufficiency. Body mass index was essentially the same in the 3 groups. Hormone users were, overall, healthier than nonusers (Table 1). However, there were no significant differences in health status and prevalence of risk factors between E and E⫹P users, although E users tended to have a higher prevalence of CAD risk factors and co-morbidities (Table 1). In unadjusted analyses, E and E⫹P users had a significantly lower likelihood of CAD than nonusers. For E users, the RR of CAD was 0.71 (95% confidence interval [CI] 0.58 to 0.84) compared with nonusers, and in E⫹P users, the corresponding RR was 0.76 (95% CI 0.54 to 0.99) (Table 2). After adjustment for age, race, family history of coronary heart disease, body mass index, smoking history, hyperlipidemia, ejection fraction, congestive heart failure, cerebrovascular accident, renal insufficiency, and diabetes, E users continued to have a significantly lower risk of CAD than nonusers (RR 0.77, 95% CI 0.69 to 0.94). However, adjustment for the same covariables considerably weakened the association between E⫹P use and CAD prevalence, yielding an RR of 0.89, with a 95% CI from 0.59 to 1.16 (Table 2). The difference in results when comparing E or E⫹P users with nonusers became even more pronounced after adjustment for aspirin and statin use (E group: RR 0.79, 95% CI 0.59 to 0.98; E⫹P group: RR 1.14; 95% CI 0.74 to 1.39) (Table 2). When the analyses were repeated with E users as a referent category, E⫹P users had a significantly higher prevalence of CAD than E users after adjustment for all the same covariables and medication use (RR 1.31, 95% CI 1.03 to 1.46) (Table 2). Hormone therapy and severity of CAD: When we examined the association of hormone use with severity of CAD, the results were consistent with those for CAD prevalence. The unadjusted OR for the E group versus nonusers, with the number of diseased vessels as an ordinal dependent variable, was 0.47 (95% CI 0.34 to 0.65) (Table 3). Similarly, for E⫹P users, the unadjusted OR was 0.50 (95% CI 0.29 to 0.87) relative to nonusers (Table 3). These data indicate an approximate 50% increase in the odds of having a higher number of diseased vessels (from none to 1, or from 1 to 2, or from 2 to 3 vessels) when comparing either group of hormone users with nonusers. After adjusting for a similar set of covariables as in the previous analysis, the association in the E⫹P group was noticeably attenuated and no longer significant (OR 0.75, 95% CI 0.37 to 1.52) (Table 3), whereas E remained inversely related to severity of CAD (OR 0.61, 95% CI 0.40 to 0.92) (Table 3). Similar to the prevalence analyses, the divergence between E and E⫹P results was intensified after adjusting for aspirin and statin use (E users: OR 0.55, MARCH 1, 2004
TABLE 1 Characteristics of Study Population Postmenopausal Hormones Risk Factors Age, mean ⫾ SD (yrs) Body mass index (mean ⫾ SD) (kg/m2) Caucasian* Smoking history Current smoker Past smoker Never smoked Hyperlipidemia Myocardial infarction† None Acute or recent Remote Diabetes mellitus Cerebrovascular accident Renal insufficiency‡ Chronic heart failure, NYHA class 0 I II III IV Left ventricular ejection fraction (mean ⫾ SD) (%)§ Systolic blood pressure, (mean ⫾ SD) (mm Hg) Aspirin use㛳 Statins use㛳 No. of narrowed coronary arteries 0 1 2 3
p Value
Nonusers (n ⫽ 633)
E (n ⫽ 163)
E⫹P (n ⫽ 47)
E vs Nonusers
E⫹P vs Nonusers
E⫹P vs E
70 ⫾ 9 28 ⫾ 6 77%
66 ⫾ 7 28 ⫾ 6 89%
65 ⫾ 7 28 ⫾ 6 95%
⬍0.0001 0.81 0.0012 0.22
⬍0.0001 0.46 0.0065 0.35
0.57 0.55 0.37 0.59
15% 27% 58% 54%
14% 34% 53% 60%
19% 34% 47% 63%
0.20 0.10
0.25 0.08
0.70 0.55
66% 23% 11% 30% 9.79% 6.98%
74% 17% 8.59% 14% 5.52% 2.45%
81% 11% 8.51% 6% 2.13% 2.13%
⬍0.0001 0.09 0.03 0.03
0.0004 0.08 0.36 0.24
0.13 0.34 0.89 0.88
72% 3.32% 7.90% 9.00% 7.90% 53 ⫾ 14 140 ⫾ 24 61% 16%
84% 1.84% 4.29% 6.13% 3.68% 55 ⫾ 12 136 ⫾ 23 66% 23%
87% 2.13% 4.26% 2.13% 4.26% 55 ⫾ 12 141 ⫾ 23 62% 19%
0.07 0.03 0.39 0.09 ⬍0.0001
0.36 0.93 0.95 0.70 0.08
0.89 0.21 0.72 0.69 0.70
52% 21% 17% 9.82%
47% 30% 15% 8.51%
32% 28% 19% 21%
*There are 568 patients in the no-hormones group, 144 in the E group and 41 in the E⫹P group. † There are 631 patient in the no-hormone group. ‡ There are 630 patient in the no-hormone group. § There are 604 patients in the no-hormone group, 158 in the E group and 44 in the E⫹P group. 㛳 There are 484 patients in the no-hormone group, 118 in the E group and 26 in the E⫹P group. NYHA ⫽ New York Heart Association.
TABLE 2 Multivariable Analysis of Association Between Hormone Use and Presence of Coronary Artery Disease (CAD) RR (95% CI) for ⱖ1 Diseased Vessels Risk Factors Unadjusted Adjusted for demographic factors, comorbidities, and CAD risk factors*† Adjusted for all of the above and medications (aspirin and statins)‡
E vs. Nonusers
E⫹P vs Nonusers
E⫹P vs E
0.71 (0.58–0.84) 0.77 (0.60–0.94) 0.79 (0.59–0.98)
0.76 (0.54–0.99) 0.92 (0.61–1.20) 1.14 (0.74–1.39)
1.07 (0.83–1.26) 1.15 (0.89–1.34) 1.31 (1.03–1.46)
*Age, race, family history, body mass index, smoking, hyperlipidemia, diabetes, congestive heart failure, history of stroke, history of renal insufficiency, blood pressure, ejection fraction. † There were 767 observations. ‡ There were 576 observations.
95% CI 0.32 to 0.94; E⫹P users: OR 1.51, 95% CI 0.51 to 4.45) (Table 3). In analyses with E users as a referent group, a pattern of more severe CAD in E⫹P users than in E users was also observed (Table 3). In all these models, the score test for the proportional odds assumption was satisfied, indicating that the ordinal logistic model was appropriate.
DISCUSSION Our results indicate that E users have less prevalent and less severe CAD than nonusers, but E⫹P users
have CAD similar to nonusers. Consistent with other observational studies, hormone users in our study were healthier and had a more favorable coronary heart disease risk profile than nonusers.15–17 In unadjusted analyses, both groups of hormone users (E and E⫹P) had a significantly lower likelihood of CAD. However, in adjusted analyses, the apparent protective effect of combination hormone therapy was explained by other covariables, e.g., E⫹P users were younger, had fewer co-morbidities and coronary heart disease risk factors, and tended to take primary prevention
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565
TABLE 3 Multivariable Analysis of Association Between Severity of Coronary Artery Disease (CAD) and Hormone Use OR (95% CI) for Higher Number of Diseased Vessels Risk Factors Unadjusted Adjusted for demographic factors, comorbidities, and CAD risk factors*† Adjusted for all of the above and medications (aspirin and statins)‡
E vs Nonusers
E⫹P vs Nonusers
E⫹P vs E
0.47 (0.34–0.65) 0.61 (0.40–0.92) 0.55 (0.32–0.94)
0.50 (0.29–0.87) 0.75 (0.37–1.52) 1.51 (0.51–4.45)
1.07 (0.58–1.95) 1.28 (0.66–2.45) 2.06 (0.91–4.66)
*Age, race, family history, body mass index, smoking, hyperlipidemia, diabetes, congestive heart failure, history of stroke, history of renal insufficiency, blood pressure, ejection fraction. † There were 767 observations. ‡ There were 576 observations.
medications more often than nonusers. In contrast, use of unopposed E remained significantly associated with less CAD. Results were similar when the number of diseased vessels was examined as a measure of CAD severity, as opposed to a dichotomous CAD variable. Although the adjusted odds for more severe CAD comparing E⫹P users with nonusers were 51% higher, those comparing E users with nonusers were 45% lower. By directly comparing E⫹P with E users, we found that E⫹P users had a higher CAD prevalence and severity than E users. It is unlikely that the protective effect of E is due to residual confounding or unmeasured factors for the following reasons. First, the E group had an overall higher risk profile than the E⫹P group; therefore, if residual confounding existed, it should have affected the E group more than the E⫹P group. This would result in a smaller benefit of E use, i.e., higher odds of CAD in E users than in E⫹P users. Second, although we did not have measures of socioeconomic status, there is reason to believe that the E and E⫹P groups should be fairly comparable in terms of education and other socioeconomic status characteristics. Few observational studies of menopausal hormone therapy have provided separate data on the effect of either E alone or E⫹P on CAD end points.18 –20 Consistent with our results, data on unopposed E therapy mostly points toward a significant reduction in CAD progression.21,22 In a recent meta-analysis by Humphrey et al,23 no risk reduction in CAD was observed in either E or E⫹P users after adjustment for socioeconomic status and other contributing factors. This study again did not examine E and E⫹P use separately. Of the secondary prevention trials of menopausal hormone therapy in women with established CAD, only 3 have presented data on unopposed E. The EStrogen in the Prevention of ReInfarction Trial (ESPRIT) examined the role of estradiol in the prevention of subsequent cardiac events in 1,017 women who survived their first myocardial infarction. In this trial, estradiol did not reduce the risk of further cardiac events.24 Similarly, the Estrogen Replacement and Atherosclerosis (ERA) trial found no effect of either E or E⫹P on the progression of coronary atherosclerosis as measured by serial coronary angiography.25 Another angiographic secondary prevention trial, the Women’s Estrogen-progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL566 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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HART), found no reduction in coronary lesions in 226 postmenopausal women with ⱖ1 diseased coronary vessel who received either E or E⫹P compared with those taking placebos.26 Of the published primary prevention trials, the most relevant trials for our population, the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) is the only trial that provided data on unopposed E for primary prevention. This was a randomized, doubleblind controlled trial of the effect of 17-estradiol on carotid artery intima-media thickness in 222 asymptomatic postmenopausal women.27 This trial found a significant reduction in the progression of atherosclerosis among estradiol users, but only in the absence of concomitant statin use. A similar randomized controlled trial, Postmenopausal HOrmone REplacement against Atherosclerosis (PHOREA), found no benefit of a combined hormone regimen toward reducing the progression of carotid intima-media thickness in women with increased carotid artery intima-media thickness at baseline.28 However, this trial did not have an E-only arm. Finally, the WHI E/progestin study of 16,608 healthy postmenopausal women found no benefits from this combination hormone regimen, but observed an excess coronary and stroke risk.13 The E-only arm of WHI, however, is still ongoing; therefore, results pertaining to unopposed E therapy in this trial are not known (Table 4). Study limitations: The number of E⫹P users was relatively small. It is unlikely that this affected our conclusions, because the estimate for the comparison of E⫹P users with nonusers was ⬎1 after multivariable analysis, whereas the estimate for E users remained well below 1. We did not have data on the different types of E (transdermal vs oral) or progestin (micronized P vs medroxyprogesterone acetate) that were used by these patients. We also cannot demonstrate temporality of association between menopausal hormone therapy use and CAD and determine the time frame of hormone use with respect to the angiography in the 2 groups of users. Another limitation is that the assessment of CAD in our study was based on visual interpretation of the lesion severity, because quantitative coronary angiographic analysis was not available. However, there is no reason to believe that visual interpretation should be biased on the basis of the hormone use, because it is unlikely that radiologists were aware of the patients’ hormonal status. Finally, our study population was composed of women reMARCH 1, 2004
⻫
⻫
⻫
⻫ ⻫
PHOREA ESPRIT ERA WAVE HERS WELLHART
See text for explanation of trial abbreviations. CEE ⫽ conjugated equine estrogen; IMT ⫽ intima-media thickness; MPA ⫽ medroxyprogesterone acetate.
⻫
⻫
17 Estradiol ⫹ gestodine 17 Estradiol CEE, CEE ⫹ MPA CEE, CEE ⫹ MPA but no between-groups comparison CEE ⫹ MPA 17 Estradiol, 17 estradiol ⫹ MPA ⻫ ⻫ ⻫ ⻫ ⻫
Secondary Prevention Trials
⻫ CEE, CEE ⫹ MPA 17 Estradiol
Primary Prevention Trials
⻫ ⻫ ⻫ ⻫ WHI EPAT
Trial
0 0 0 0 0 0
?/0 ⫹
Benefit Comparison Between Hormone Regimens (E vs EP) Tested Type of Hormone Regimen(s) Studied Unopposed Estrogen Tested Coronary Heart Disease Events End Points
Carotid IMT Coronary Angiography
TABLE 4 Comparison of Randomized Clinical Trials
ferred for coronary angiography; therefore, our study may not be generalizable to all women. Because we are dealing with a referral population, the possibility of different thresholds of referral and evaluation between hormone users and nonusers cannot be excluded. Despite these limitations, this is the first study addressing this question in a large sample of women with objective assessment of CAD. Conclusions: Our results suggest that the addition of P in treatment therapies may attenuate a potentially beneficial effect of unopposed E toward coronary heart disease risk. Further experimental studies are required to investigate whether the apparent angiographic benefit of E monotherapy observed in this study is truly due to E therapy, and whether this association results in an actual reduction of coronary heart disease events. Until this evidence is obtained, women should be discouraged from using any hormone regimens for the sole purpose of coronary heart disease prevention.29 1. Chambliss KL, Shaul PW. Estrogen modulation of endothelial nitric oxide synthase. Endocr Rev 2002;23:665–686. 2. Gerhard M, Walsh BW, Tawakol A, Haley EA, Creager SJ, Seely EW, Ganz P, Creager MA. Estradiol therapy combined with progesterone and endotheliumdependent vasodilation in postmenopausal women. Circulation 1998;98:1158 – 1163. 3. Godsland IF. Hormone replacement therapy and carbohydrate metabolism in cardiovascular risk. In: Lobo RA, ed. Treatment of the Postmenopausal Women: Basic and Clinical Aspects. Philadelphia: Lippincott Williams & Wilkins, 1999: 391–395. 4. Lobo RA, Pickar JH, Wild RA, Walsh B, Hirvonen E. Metabolic impact of adding medroxyprogesterone acetate to conjugated estrogen therapy in postmenopausal women. The Menopause Study Group. Obstet Gynecol 1994;84:987–995. 5. Mercuro G, Pitzalis L, Podda A, Zoncu S, Pilia I, Melis GB, Cherchi A. Effects of acute administration of natural progesterone on peripheral vascular responsiveness in healthy postmenopausal women. Am J Cardiol 1999;84:214 –218. 6. Rosano GM, Sarais C, Zoncu S, Mercuro G. The relative effects of progesterone and progestins in hormone replacement therapy. Hum Reprod 2000;15: 60 –73. 7. Rosselli M, Imthurn B, Keller PJ, Jackson EK, Dubey RK. Circulating nitric oxide (nitrite/nitrate) levels in postmenopausal women substituted with 17estradiol and norethisterone acetate: a two-year follow-up study. Hypertension 1995;25:848 –853. 8. Sullivan JM, Shala BA, Miller LA, Lerner JL, McBrayer JD. Progestin enhances vasoconstrictor responses in postmenopausal women receiving estrogen replacement therapy. Menopause 1995;2:193–199. 9. Vogel RA, Corretti MC. Estrogens, progestins, and heart disease: can endothelial function divine the benefit? Circulation 1998;97:1223–1226. 10. Walsh B, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks F. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991;325:1196 –1204. 11. Williams JK, Honore EK, Washburn SA, Clarkson TB. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol 1994;24:1757–1761. 12. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49 –57. 13. Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–333. 14. Zhang J, Yu KF. What’s the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA 1998;280:1690 –1691. 15. Matthews KA, Kuller LH, Wing RR, Meilahn EN, Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers? Am J Epidemiol 1996;143:971–978. 16. Humphrey LL, Nelson HD, Chan BK, Nygren P, Allan J, Teutsch S. Relationship between hormone replacement therapy, socioeconomic status, and coronary heart disease. JAMA 2003;289:45–46. 17. Nelson HD, Humphrey LL, Nygren P, Teutsch SM, Allan JD. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002;288:872– 881.
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18. Hong MK, Romm PA, Reagan K, Green CE, Rackley CE. Effects of estrogen replacement therapy on serum lipid values and angiographically defined coronary artery disease in postmenopausal women. Am J Cardiol 1992;69:176 –178. 19. McFarland KF, Boniface ME, Hornung CA, Earnhardt W, Humphries JO. Risk factors and noncontraceptive estrogen use in women with and without coronary disease. Am Heart J 1989;117:1209 –1214. 20. Sullivan JM, Vander Zwaag R, Lemp GF, Hughes JP, Maddock V, Kroetz FW, Ramanathan KB, Mirvis DM. Postmenopausal estrogen use and coronary atherosclerosis. Ann Intern Med 1988;108:358 –363. 21. Falkeborn M, Persson I, Adami HO, Bergstrom R, Eaker E, Lithell H, Mohsen R, Naessen T. The risk of acute myocardial infarction after oestrogen and oestrogen-progestogen replacement. Br J Obstet Gynaecol 1992;99:821–828. 22. Grodstein FS, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med 2000;133:933– 941. 23. Humphrey LL, Chan BK, Sox HC. Postmenopausal hormone replacement therapy and the primary prevention of cardiovascular disease. Ann Intern Med 2002;137:273–289. 24. Cherry N, Gilmour K, Hannaford P, Heagerty A, Khan MA, Kitchener H, McNamee R, Elstein M, Kay C, Seif M, Buckley H, The ET. Oestrogen therapy
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for prevention of reinfarction in postmenopausal women: a randomised placebo controlled trial. Lancet 2002;360:2001–2008. 25. Herrington DM, Reboussin DM, Brosnihan KB, Sharp PC, Shumaker SA, Snyder TE, Furberg CD, Kowalchuk GJ, Stuckey TD, et al. Effects of estrogen replacement on the progression of coronary-artery atherosclerosis. N Engl J Med 2000;343:522–529. 26. Hodis HN, Mack WJ, Azen SP, Lobo RA, Shoupe D, Mahrer PR, Faxon DP, Cashin-Hemphill L, Sanmarco ME, French WJ, et al. Hormone therapy and the progression of coronary artery atherosclerosis in postmenopausal women. N Engl J Med 2003;349:535–545. 27. Hodis HN, Mack WJ, Lobo RA, Shoupe D, Sevanian A, Mahrer PR, Selzer RH, Liu CR, Liu CH, Azen SP. Estrogen in the prevention of atherosclerosis. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2001;135: 939 –953. 28. Angerer P, Stork S, Kothny W, Schmitt P, von Schacky C. Effect of oral postmenopausal hormone replacement on progression of atherosclerosis: a randomized, controlled trial. Arterioscler Thromb Vasc Biol 2001;21:262–268. 29. FDA. The estrogen and progestin dilemma: new advice, and labeling guidelines. Available at: http://www.fda.gov/fdac/features/2003/203_estrogen.html. Accessed on Jan. 15, 2004.
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