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Myocardial infarction during menses: lessons from trials and errors

2003; Elsevier BV; Volume: 114; Issue: 7 Linguagem: Inglês

10.1016/s0002-9343(03)00126-8

1555-7162

Deborah Grady,

Endometrial and Cervical Cancer Treatments

The history of changes in our beliefs about the effect of estrogen on the risk of coronary disease teaches several important clinical lessons. In the early 1960s, the simple facts that endogenous estrogen levels are higher in premenopausal women than in postmenopausal women or in men, and that premenopausal women rarely experience myocardial infarction, promoted the belief that treatment with estrogen might reduce the risk of coronary heart disease. About this time, it also became clear that estrogen treatment improves the lipoprotein profile, increasing high-density lipoprotein cholesterol and lowering low-density lipoprotein cholesterol levels. Based on this evidence, the National Institutes of Health conducted a large randomized trial of the effect of estrogen therapy on the risk of coronary events (1Coronary Drug Project Research GroupThe Coronary Drug Project—findings leading to discontinuation of the 2.5-mg/day estrogen group.JAMA. 1973; 226: 652-657Crossref PubMed Scopus (398) Google Scholar). About 8700 men with previous myocardial infarction were assigned randomly to five cholesterol-lowering drugs (including two doses of conjugated estrogen) or placebo. The estrogen arms were stopped prematurely because of an increase in the risk of venous thromboembolic events and substantial adverse effects. In the 1980s, there was renewed interest in estrogen for the prevention of coronary heart disease when several large observational studies suggested that the risk was lower in women who had used postmenopausal estrogen than in those who had not (2Stampfer M. Willett W.C. Colditz G.A. Rosner B. Speizer F.E. Hennekens C.H. A prospective study of postmenopausal estrogen therapy and coronary heart disease.N Engl J Med. 1985; 313: 1044-1049Crossref PubMed Scopus (739) Google Scholar). Subsequently, multiple case-control and cohort studies reported a 30% to 50% lower risk among women taking postmenopausal estrogen or estrogen plus progestin compared with nonusers (3Barrett-Connor E. Grady D. Hormone replacement therapy, heart disease, and other considerations.Annu Rev Public Health. 1998; 19: 55-72Crossref PubMed Scopus (527) Google Scholar). Concurrently, small randomized trials also demonstrated that treatment with estrogen prolongs treadmill exercise time among women with coronary heart disease, prevents coronary vasoconstriction in women with atherosclerosis, and retards progression of coronary atherosclerosis in animals (4Mendelsohn M.E. Karas R.H. The protective effects of estrogen on the cardiovascular system.N Engl J Med. 1999; 340: 1801-1811Crossref PubMed Scopus (2488) Google Scholar). Recently, however, large randomized controlled trials have found that postmenopausal estrogen either has no overall benefit (5Grady D. Herrington D. Vittner V. 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: 49-57Crossref PubMed Scopus (1550) Google Scholar, 6Viscoli C.M. Brass L.M. Kernan W.N. Sarrel P.M. Suissa S. Horwitz R.I. A clinical trial of estrogen-replacement therapy after ischemic stroke.N Engl J Med. 2001; 345: 1243-1249Crossref PubMed Scopus (802) Google Scholar) or increases the risk of cardiovascular events (7Writing Group for the Women’s Health Initiative InvestigatorsRisks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Scopus (13914) Google Scholar), raising questions about why the findings of the observational studies appear to have been wrong. It may have been that estrogen users, even before beginning treatment, are healthier and have lower cardiovascular risk than do nonusers (8Matthews K.A. Kuller L.H. Wing R.R. Meilahn E.N. Plantinga P. Prior to use of estrogen replacement therapy, are users healthier than nonusers?.Am J Epidemiol. 1996; 143: 971-978Crossref PubMed Scopus (459) Google Scholar). Although many of the observational studies attempted to adjust statistically for differences between women who used estrogen and those who did not, some important variables may not have been measured. For example, studies that adjusted for socioeconomic status, a major predictor of risk of coronary heart disease, did not find an association between estrogen use and lower risk (9Nelson H.D. Humphrey L.L. Nygren P. Teutsch S.M. Allan J.D. Postmenopausal hormone replacement therapy. Scientific review.JAMA. 2002; 288: 872-881Crossref PubMed Scopus (899) Google Scholar). Were the findings of studies showing that estrogen improves lipoprotein levels, prevents vasoconstriction, and retards atherosclerosis also erroneous? These effects have been demonstrated in randomized trials, reducing the likelihood of baseline differences between estrogen users and nonusers (4Mendelsohn M.E. Karas R.H. The protective effects of estrogen on the cardiovascular system.N Engl J Med. 1999; 340: 1801-1811Crossref PubMed Scopus (2488) Google Scholar). Some of the beneficial effects may occur only with acute treatment at pharmacologic doses. Perhaps estrogen does not reduce the risk of coronary heart disease because the effects of estrogen differ with chronic and acute treatment. In this issue of the Journal, Hamelin et al. (10Hamelin B.A. Méthot J. Arsenault M. et al.Influence of the menstrual cycle on the timing of acute coronary events in premenopausal women.Am J Med. 2003; 114: 599-602Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar) present data on 27 premenopausal women admitted with the diagnosis of myocardial infarction or unstable angina. The ischemic event occurred during the first 6 days of the menstrual cycle (menstrual phase) in 19 women and on days 7 to 14 (follicular phase) in 8 women. No events occurred in the last half (luteal phase) of the cycle (P <0.00001). Because endogenous estradiol levels decline from the highest at midcycle to the lowest during menses, the authors concluded that acute declines in estrogen level might increase the risk of ischemic events, perhaps by effects on local vasoactive substances such as endothelin-1 and endothelium-derived relaxing factor (nitric oxide). Although a small observational study, the findings are interesting because they suggest that acute changes in estrogen levels may be more important than stable absolute levels, and that women develop tolerance to coronary effects of estrogen over the course of a few days or that homeostatic systems somehow downregulate the effects of estrogen with chronic exposure. The development of tolerance to the vasodilatory effects of nitroglycerin is a classic example of how acute exposure to a drug can differ from chronic exposure. This is a particularly relevant example, because acute estrogen exposure results in local production and release of endothelium-derived relaxing factor, a potent arterial vasodilator that is chemically identical to nitric oxide (4Mendelsohn M.E. Karas R.H. The protective effects of estrogen on the cardiovascular system.N Engl J Med. 1999; 340: 1801-1811Crossref PubMed Scopus (2488) Google Scholar). Thus, acute treatment might result in coronary vasodilation, and acute withdrawal might lead to vasoconstriction and coronary ischemia. Acute treatment with estrogen prolongs the length of time that women with coronary disease are able to walk on a treadmill (11Rosano G.M.C. Sarrel P.M. Poole-Wilson P.A. Collins P. Beneficial effect of oestrogen on exercise-induced myocardial ischemia in women with coronary artery disease.Lancet. 1993; 342: 133-136Abstract PubMed Scopus (422) Google Scholar), whereas chronic treatment does not (12Sbarouni E. Kyriakides Z.S. Nikolaou N. Kremastinos D.T. Estrogen replacement therapy and exercise performance in postmenopausal women with coronary artery disease.Am J Cardiol. 1997; 79: 87-89Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). Similarly, acute treatment results in increased coronary blood flow in women with atherosclerosis (13Reis S.E. Gloth S.T. Blumenthal R.S. et al.Ethinyl estradiol acutely attenuates abnormal coronary vasomotor responses to acetylcholine in postmenopausal women.Circulation. 1994; 89: 52-60Crossref PubMed Scopus (485) Google Scholar), unlike chronic treatment (14Blumenthal R. Brinker J. Resar J. et al.Long-term estrogen therapy abolishes acute estrogen-induced coronary flow augmentation in postmenopausal women.Am Heart J. 1997; 133: 323-328Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). If it is true that acute changes in endogenous estrogen level affect the risk of coronary heart disease but chronic changes do not, we would not expect to see a reduction in the risk of coronary events among postmenopausal women who are long-term hormone users. Although interesting, it is unlikely that differences in the acute and chronic effects of estrogen explain why the reduction in the risk of coronary events predicted by the findings of mechanistic studies is not observed in randomized trials. If an acute decrease in endogenous estrogen level is associated with coronary vasoconstriction and ischemia, we might also expect to see an increased risk of myocardial infarction associated with termination of pregnancy, during the placebo phase of oral contraceptive use, for a brief period around menopause, and with stopping postmenopausal hormone therapy. To my knowledge, none of these temporary increases in risk have been observed. Similarly, we might expect that starting postmenopausal hormone therapy would be associated with at least a brief reduction in the risk of coronary events. In fact, there appears to be an increased risk of cardiovascular events shortly after starting therapy (6Viscoli C.M. Brass L.M. Kernan W.N. Sarrel P.M. Suissa S. Horwitz R.I. A clinical trial of estrogen-replacement therapy after ischemic stroke.N Engl J Med. 2001; 345: 1243-1249Crossref PubMed Scopus (802) Google Scholar, 15Hulley S. Grady D. Bush T. et al.Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA. 1998; 280: 605-613Crossref PubMed Scopus (5667) Google Scholar). An alternative explanation for the discrepancy between the findings of mechanistic studies and randomized trials is that estrogen treatment activates multiple pathways, some that decrease coronary event risk and others that increase it. The balance of these effects appears to be relatively neutral in women with cardiovascular disease (6Viscoli C.M. Brass L.M. Kernan W.N. Sarrel P.M. Suissa S. Horwitz R.I. A clinical trial of estrogen-replacement therapy after ischemic stroke.N Engl J Med. 2001; 345: 1243-1249Crossref PubMed Scopus (802) Google Scholar, 15Hulley S. Grady D. Bush T. et al.Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.JAMA. 1998; 280: 605-613Crossref PubMed Scopus (5667) Google Scholar) and harmful in those without known cardiovascular disease (7Writing Group for the Women’s Health Initiative InvestigatorsRisks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial.JAMA. 2002; 288: 321-333Crossref PubMed Scopus (13914) Google Scholar). Estrogen therapy might result in an increased risk of coronary events by increasing inflammatory markers such as C-reactive protein (16Paul S. Dean R. Tracy R. Cox D. Walsh B. Anderson P. Effects of raloxifene and hormone replacement therapy on homocysteine and C-reactive protein levels in postmenopausal women.Circulation. 1998; 98: I7-I8Google Scholar) or the risk of arterial or venous thrombosis (17Grady D. Sawaya G. Postmenopausal hormone therapy increases risk of deep vein thrombosis and pulmonary embolism.Am J Med. 1998; 105: 41-43Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar). Understanding how estrogen causes inflammation and thrombosis might allow us to develop selective estrogens that are not associated with these adverse effects, resulting in a net reduction in the risk of coronary heart disease. Some of the lessons learned from the studies of the effect of estrogen on coronary event risk are broadly applicable. First, simple theories are often wrong. Second, the results of observational studies can be clinically misleading. Sometimes it is not possible to confirm the findings of observational studies in randomized trials. But when possible, randomized trials should be conducted, especially to document that the benefit of a preventive treatment outweighs the risks. Finally, studies of mechanisms are scientifically interesting, but can be clinically misleading if a drug has a variety of effects, some of which are not well understood.