Correspondence
Coronary Artery Disease in Men and Women
N Engl J Med 1999; 341:1931-1935December 16, 1999
- Article
To the Editor:
Vaccarino et al. (July 22 issue)1 show that younger women, but not older women, have higher rates of death during hospitalization after acute myocardial infarction than men of the same age. Potential reasons for their findings include differences between men and women with respect to the aggressiveness of the disease, the treatment strategies used, and rates of death before hospitalization. Studies from the World Health Organization's Monitoring Trends and Determinants in Cardiovascular Disease (MONICA) project have shown that a higher rate of death from acute myocardial infarction during hospitalization among women may be balanced by a higher rate of death before hospitalization among men.2,3 We would like to shed further light on these issues, using information from a population-based national registry of incident cases of acute myocardial infarction in Sweden.
Sweden has a national registry for acute myocardial infarction, which covers all Swedish citizens discharged from hospitals with a diagnosis of acute myocardial infarction and those who have died with a diagnosis of acute myocardial infarction.4 The data in the registry are based on the linkage of records between the national registry of hospital discharges and national data on causes of death. The registry for acute myocardial infarction currently contains data on approximately 303,000 persons who were given a diagnosis of acute myocardial infarction in 1987 through 1995. The completeness of the registry and the validity of the diagnostic information have been evaluated and found to be of high quality.5
The outcome measure in our analysis was the case fatality rate within 28 days after an acute myocardial infarction, irrespective of whether the death occurred while the patient was in or out of hospital. We were able to determine the case fatality rate among all patients with incident acute myocardial infarction, including those who were not hospitalized at the time of death. Our analyses confirm the findings of Vaccarino et al. that younger women, but not older women, have higher case fatality rates within 28 days after hospitalization than men of the same age (Figure 1Figure 1
Case Fatality within 28 Days after Hospitalization for Patients with Acute Myocardial Infarction in Sweden, 1987 to 1995.). In analyses in which deaths from acute myocardial infarction in patients who were not hospitalized at the time of death were included, this sex difference was still present among the patients who were 30 to 49 years of age. Among hospitalized patients, women who were 50 to 69 years of age had a higher case fatality rate than men of similar age; among nonhospitalized patients, no such difference was observed. Our results for this age group are consistent with those of the MONICA project.2,3 A majority of deaths from acute myocardial infarction occur outside the hospital, and it is important to take these deaths into account in analyses of case fatality. Our results support the conclusion that younger women are at higher risk for death after an acute myocardial infarction than men of similar age. They also indicate that, among middle-aged patients, other explanations (e.g., sex differences in patterns of seeking care) may account for the differences in mortality during hospitalization between men and women.
5 ReferencesMåns Rosén, Ph.D.
Curt-Lennart Spetz, B.A.
National Board of Health and Welfare, S-106 30 Stockholm, SwedenNiklas Hammar, Ph.D.
Karolinska Institute, S-171 76 Stockholm, Sweden1
Vaccarino V ,Parsons L ,Every NR ,Barron HV ,Krumholz HM . Sex-based differences in early mortality after myocardial infarction. N Engl J Med 1999;341:217-225
Full Text | Web of Science | Medline2
Sonke GS ,Beaglehole R ,Stewart AW ,Jackson R ,Stewart FM . Sex differences in case fatality before and after admission to hospital after acute cardiac events: analysis of community based coronary heart disease register. BMJ 1996;313:853-855
CrossRef | Web of Science | Medline3
Tunstall-Pedoe H ,Morrison C ,Woodward M ,Fitzpatrick B ,Watt G . Sex differences in myocardial infarction and coronary deaths in the Scottish MONICA population of Glasgow 1985 to 1991: presentation, diagnosis, treatment, and 28-day case fatality of 3991 events in men and 1551 events in women. Circulation 1996;93:1981-1982
Web of Science | Medline4
Hjärtinfarkter 1987-1996. Stockholm, Sweden: National Board of Health and Welfare, 1998:6.
5
Alfredsson L, Hammar N, Hodell A, et al. Värdering av diagnoskvaliteten för akut hjärtinfarkt i tre svenska län 1995. Stockholm, Sweden: National Board of Health and Welfare, October 1997.
To the Editor:
Vaccarino et al. reported that women under the age of 75 years who have myocardial infarction are a high-risk group deserving of special study. Specifically, Vaccarino et al. demonstrated that in each age group from less than 50 years to 70 to 74 years, women with myocardial infarction had higher in-hospital mortality than men. Thus, in contrast to previous reports on this topic,1 age alone does not appear to explain the higher mortality after myocardial infarction among women than among men.
We call attention to previously reported results that are nearly identical to those of Vaccarino et al. We have published two reports on this topic,2,3 including a breakdown of in-hospital mortality according to five-year age groups, beginning with 44 years of age or younger and continuing up to 80 years or older.3 We, too, found that the age-adjusted in-hospital mortality among women was about 1.5 times as high as that among men — and that this difference was present in every age group except 45 to 49 years and 80 years or older (Table 1Table 1
In-Hospital Mortality after Acute Myocardial Infarction, According to Age and Sex.). Further multivariate adjustment for prognostically significant covariates reduced the relative risk to about 1.2, but the increased mortality among women remained statistically significant. We, too, concluded that women represent a high-risk group at every age except the oldest.We agree with the findings of Vaccarino et al. and with the accompanying editorial by Wexler4 that the data raise provocative questions about the role of sex hormones and other factors in the pathophysiology of ischemic heart disease.
4 ReferencesPhilip Greenland, M.D.
Northwestern University Medical School, Chicago, IL 60611Uri Goldbourt, Ph.D.
Tel Aviv University, 69978 Tel Aviv, Israel1
Vaccarino V ,Krumholz HM ,Berkman LF ,Horwitz RI . Sex differences in mortality after myocardial infarction: is there evidence for an increased risk for women? Circulation 1995;91:1861-1871
Web of Science | Medline2
Greenland P ,Reicher-Reiss H ,Goldbourt U ,Behar S . In-hospital and 1-year mortality in 1,524 women after myocardial infarction: comparison with 4,315 men. Circulation 1991;83:484-491
Web of Science | Medline3
Goldbourt U ,Greenland P . Sex differences in men and women after myocardial infarction. Circulation 1996;93:1260-1261
Web of Science | Medline4
Wexler LF . Studies of acute coronary syndromes in women -- lessons for everyone. N Engl J Med 1999;341:275-276
Full Text | Web of Science | Medline
To the Editor:
In their article, Hochman et al. (July 22 issue)1 state: “Women and men with acute coronary syndromes had different clinical profiles, presentations, and outcomes. These differences could not be entirely accounted for by differences in base-line characteristics and may reflect pathophysiologic and anatomical differences between men and women.” We disagree with their conclusion.
We conducted a study to determine whether women had higher rates of morbidity and mortality than men after acute myocardial infarction. We analyzed a total of 220 patients who were admitted to the coronary care unit of a suburban teaching hospital for acute myocardial infarction between July 1, 1996, and June 30, 1997. The results of our study are very similar to those of Hochman et al. For example, the women were older than the men (mean [±SD] age, 73±14 vs. 68±13 years), more commonly had diabetes (40 percent vs. 15 percent), smoked less (33 percent vs. 55 percent), and had fewer Q-wave myocardial infarctions (25 percent vs. 37 percent). In addition, the women had a higher in-hospital mortality rate than did the men (10 percent vs. 7 percent).
In our study, we discovered that women were treated much less aggressively than men (Table 1Table 1
Management Methods after Myocardial Infarction in Men and Women.). Fewer women than men were treated with aspirin, beta-blockers, angiotensin-converting–enzyme inhibitors, and lipid-lowering drugs. In addition, fewer women than men with acute myocardial infarction were sent to local cardiac centers for further evaluation or treatment.Data from a recent, large-scale survey also showed that treatment with aspirin, heparin, and beta-blockers was less frequent in women with acute myocardial infarction than in men.2 The fact that women with acute myocardial infarction are treated less aggressively than men, rather than pathophysiologic and anatomical differences between women and men, as Hochman et al. proposed, may be responsible for the higher mortality rate among women.
2 ReferencesLequn Cao, M.D.
University of Illinois at Chicago, Chicago, IL 60612Wei Song, M.D.
Temple University, Philadelphia, PA 191401
Hochman JS ,Tamis JE ,Thompson TD , et al. Sex, clinical presentation, and outcome in patients with acute coronary syndromes. N Engl J Med 1999;341:226-232
Full Text | Web of Science | Medline2
Chandra NC ,Ziegelstein RC ,Roger WJ , et al. Observations of the treatment of women in the United States with myocardial infarction: a report from the National Registry of Myocardial Infarction-I. Arch Intern Med 1998;158:981-988
CrossRef | Web of Science | Medline
To the Editor:
We congratulate Vaccarino et al. and Hochman et al. on their illuminating studies of the role of sex differences in outcomes of coronary artery disease. In the accompanying editorial, Wexler hypothesizes that there is a protective factor that delays the development of atherosclerosis in women and accounts for the observation that women, as a group, have myocardial infarctions at a later age than men. She asserts that “the obvious and best candidate for the putative protective factor is estrogen.”1 She cites as supporting evidence the finding that the differences between men and women with regard to coronary artery disease tend to diminish after women reach menopause.
Although we agree that estrogen may be the most obvious factor responsible for this observation, it may not be the only one, or even the most important one. A growing body of literature suggests that iron has a role in the development of atherosclerosis and ischemic heart disease.2 Iron is a powerful oxidant that mediates lipid-peroxidation reactions to form oxidized low-density lipoprotein cholesterol, which in turn is implicated in the initiation and progression of atherosclerosis. The results of epidemiologic studies show a positive association between total body iron stores and the risk of myocardial infarction and peripheral vascular disease.3 Throughout the premenopausal years, women have a built-in mechanism for iron reduction through menstruation. Consequently, premenopausal women have lower body iron stores, as measured by serum ferritin levels, than men of similar age. The ferritin levels in men rise progressively over time after the adolescent growth spurt; however, women do not have a similar increase in total body iron until after menopause. Interestingly, the change in cardiovascular risk over time for women parallels the increase in total body stores in much the same way as it parallels the decrease in estrogen.
A study by Centerwall in 19814 showed that the incidence of coronary heart disease increased by a factor of three during the remaining premenopausal years among women who underwent a simple hysterectomy. Since the ovaries, and therefore estrogen production, were left intact, an explanation other than a change in hormone status is needed to account for the increase in cardiovascular disease. Similar observations have been made about carotid-artery atherosclerosis.3 An increased accumulation of iron owing to cessation of menses is one explanation that is consistent with these observations.
4 ReferencesDeborah L. Ornstein, M.D.
Wilford Hall Medical Center, Lackland AFB, TX 78236Leo R. Zacharski, M.D.
Veterans Affairs Medical and Regional Office Center, White River Junction, VT 050091
Wexler LF . Studies of acute coronary syndromes in women -- lessons for everyone. N Engl J Med 1999;341:275-276
Full Text | Web of Science | Medline2
Sullivan JL . Iron versus cholesterol -- perspectives on the iron and heart disease debate. J Clin Epidemiol 1996;49:1345-1352
CrossRef | Web of Science | Medline3
Kiechl S ,Willeit J ,Egger G ,Poewe W ,Oberhollenzer F . Body iron stores and the risk of carotid atherosclerosis: prospective results from the Bruneck study. Circulation 1997;96:3300-3307
Web of Science | Medline4
Centerwall BS . Premenopausal hysterectomy and cardiovascular disease. Am J Obstet Gynecol 1981;139:58-61
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: My colleagues and I thank Rosén et al. and Greenland and Goldbourt for the data they provide, which are consistent with our findings. The data from the Swedish national registry are important, because they indicate that different rates of out-of-hospital deaths between women and men are not likely to be an explanation for the higher in-hospital mortality among young and middle-aged women, as compared with that among men. Since we did not have information on deaths from myocardial infarction among persons who were not hospitalized, we could not address this issue in our study.
In our first paper reporting an interaction between sex and age in terms of mortality after myocardial infarction,1 we cited an article by Greenland et al., as well as several other studies that reported data on mortality rates after myocardial infarction stratified according to age and sex. The data presented in the original report by Greenland et al.2 and in a letter to the editor by Goldbourt and Greenland,3 as well as in many other studies (for a complete list, see our 1998 report1), suggested that there is an interaction between sex and age. However, this observation was not emphasized and no comment was offered about it. In addition, effect modification was not tested and just one overall estimate of the effect of sex was given, rather than estimates according to age group. Nonetheless, these previous reports were very useful, since they helped us formulate our hypothesis of an interaction between sex and age with respect to mortality after myocardial infarction.
We also thank Ornstein and Zacharski for their useful comments. The hypothesized connection between increased iron stores and coronary heart disease has been controversial. However, recent evidence that heterozygosity for the hereditary hemochromatosis gene increases the risk of coronary heart disease brings new life to this hypothesis.4,5 A causal relation between iron stores and coronary heart disease needs to be substantiated by the results of clinical trials indicating that iron depletion can decrease the rate of death from cardiovascular causes among persons at risk. Until then, however, we agree that the “iron hypothesis” should be considered as a possible explanation for the apparent protection of premenopausal women against the development of coronary atherosclerosis.
This same mechanism could also contribute to the higher risk of atherosclerosis among women who undergo premature menopause, as compared with premenopausal women. We did not have information on menopausal status; therefore, it may well be that a proportion of the younger women with myocardial infarction in our study had undergone premature menopause. However, this hypothesis, like the estrogen-based hypotheses, is not necessarily useful in explaining why these women have a higher risk of death after an acute myocardial infarction than men of similar age — among such women the risk should be equal to that among men.
5 ReferencesViola Vaccarino, M.D., Ph.D.
Yale University School of Medicine, New Haven, CT 065201
Vaccarino V ,Horwitz RI ,Meehan TP ,Petrillo MK ,Radford MJ ,Krumholz HM . Sex differences in mortality after myocardial infarction: evidence for a sex-age interaction. Arch Intern Med 1998;158:2054-2062
CrossRef | Web of Science | Medline2
Greenland P ,Reicher-Reiss H ,Goldbourt U ,Behar S . In-hospital and 1-year mortality in 1,524 women after myocardial infarction: comparison with 4,315 men. Circulation 1991;83:484-491
Web of Science | Medline3
Goldbourt U ,Greenland P . Sex differences in men and women after myocardial infarction. Circulation 1996;93:1260-1261
Web of Science | Medline4
Roest M ,van der Schouw YT ,de Valk B , et al. Heterozygosity for a hereditary hemochromatosis gene is associated with cardiovascular death in women. Circulation 1999;100:1268-1273
Web of Science | Medline5
Tuomainen TP ,Kontula K ,Nyyssonen K ,Lakka TA ,Helio T ,Salonen JT . Increased risk of acute myocardial infarction in carriers of the hemochromatosis gene Cys282Tyr mutation: a prospective cohort study of men in eastern Finland. Circulation 1999;100:1274-1279
Web of Science | Medline
Author/Editor Response
We thank Cao and Song for sharing their important data and highlighting the possible undertreatment of women. We recognize that such undertreatment has occurred in clinical practice. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb study1 had uniform treatment recommendations concerning antithrombotic and antiplatelet therapy for all patients. In all three coronary syndromes, 96 to 97 percent of the women and men in the GUSTO IIb study received aspirin and all the patients received full intravenous anticoagulant therapy. Beta-blockers were administered to 70 to 77 percent of the patients (depending on the type of acute coronary syndrome the patient had) and at rates that were similar for men and women. Angiotensin-converting–enzyme inhibitors were also administered to men and women at similar rates.
Angioplasty was performed in 32 percent of the men and in 31 percent of the women with myocardial infarction who had ST-segment elevation and 22 percent of the men and 20 percent of the women with myocardial infarction who did not have ST-segment elevation. Rates of coronary-artery bypass grafting were also similar for men and women for treatment of these syndromes. Because women with unstable angina more frequently had no clinically significant coronary stenosis (31 percent, vs. 14 percent for men), they underwent percutaneous transluminal coronary angioplasty and coronary-artery bypass grafting less often than men (percutaneous transluminal coronary angioplasty, 16 percent vs. 20 percent; coronary-artery bypass grafting, 11 percent vs. 16 percent). Women with unstable angina did significantly better than men.
In conclusion, the differences in outcome between men and women in our study were not due to differences in treatment. There are other data that reflect lower rates of use of important medications, such as aspirin and beta-blockers, among women. This fact requires attention and correction in clinical practice. Although Vaccarino et al.2 reported lower rates of administration of important medications to women, differences in treatment, medical history, and the clinical severity of the myocardial infarction accounted for only about one third of the difference in risk between men and women. We believe that we need further investigation to understand other differences between the sexes in order to improve the management of acute coronary syndromes in both women and men.
2 ReferencesJudith S. Hochman, M.D.
St. Luke's–Roosevelt Hospital Center, New York, NY 10025Trevor D. Thompson, B.S.
Duke Clinical Research Institute, Durham, NC 277101
The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators
Full Text | Web of Science | Medline2
Vaccarino V ,Parsons L ,Every NR ,Barron HV ,Krumholz HM . Sex-based differences in early mortality after myocardial infarction. N Engl J Med 1999;341:217-225
Full Text | Web of Science | Medline
