Impact of history of diabetes mellitus on hospital mortality in men and women with first acute myocardial infarction

Women appear to be particularly susceptible to adverse long-term consequences of diabetes mellitus on coronary heart disease risk. Diabetes mellitus is a stronger risk factor in women than in men for coronary heart disease incidence and mortality,1Heyden S. Heiss G. Bartel A.G. Hames C.G. Sex differences in coronary mortality among diabetics in Evans County, Georgia.J Chron Dis. 1980; 33: 265-273Abstract Full Text PDF PubMed Scopus (118) Google Scholar, 2Kannel W.B. McGee D.L. Diabetes and glucose tolerance as risk factors for cardiovascular disease The Framingham Study.Diabetes Care. 1979; 2: 120-126Crossref PubMed Scopus (1040) Google Scholar, 3Barrett-Connor E. Cohn B.A. Wingard D.L. Eldestein S.L. Why is diabetes mellitus a stronger risk factor for fatal ischemic heart disease in women than in men? The Rancho Bernardo Study.JAMA. 1991; 265: 627-631Crossref PubMed Scopus (639) Google Scholar, 4Pan W. Cedres L.B. Liu K. Dyer A. Schoenberger J.A. Shekelle R.B. Stamler R. Smith D. Collette P. Stamler J. Relationship of clinical diabetes and asymptomatic hyperglycemia to risk of coronary heart disease mortality in men and women.Am J Epidemiol. 1986; 123: 504-516Crossref PubMed Scopus (296) Google Scholar as well as a for long-term mortality after acute myocardial infarction (AMI).5Abbott R.D. Donahue R.P. Kannel W.B. Wilson P.W.F. The impact of diabetes on survival following myocardial infarction in men vs women.JAMA. 1988; 260: 3456-3460Crossref PubMed Scopus (419) Google Scholar, 6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar, 7Miettinen H. Lehto S. Salomaa V. Mahonen M. Niemela M. Haffner S.M. Pyorala K. Tuomilehto J. Impact of diabetes on mortality after the first myocardial infarction.Diabetes Care. 1998; 21: 69-75Crossref PubMed Scopus (616) Google Scholar, 8Behar S. Boyko V. Reicher-Reiss H. Goldbourt U. Ten-year survival after acute myocardial infarction comparison of patients with and without diabetes.Am Heart J. 1997; 133: 290-296Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Whether diabetes is associated with a differential effect in women and in men also in the short term after AMI, however, is less clear. Whereas some studies support this notion,7Miettinen H. Lehto S. Salomaa V. Mahonen M. Niemela M. Haffner S.M. Pyorala K. Tuomilehto J. Impact of diabetes on mortality after the first myocardial infarction.Diabetes Care. 1998; 21: 69-75Crossref PubMed Scopus (616) Google Scholar, 9Chun B.Y. Dobson A.J. Heller R.F. The impact of diabetes on survival among patients with first myocardial infarction.Diabetes Care. 1997; 20: 704-708Crossref PubMed Scopus (92) Google Scholar others have found small or no sex differences in the effect of diabetes on short-term mortality6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar, 8Behar S. Boyko V. Reicher-Reiss H. Goldbourt U. Ten-year survival after acute myocardial infarction comparison of patients with and without diabetes.Am Heart J. 1997; 133: 290-296Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar or an even stronger effect of diabetes in men.10Cooper R.S. Pacold I.V. Ford E.S. Age-related differences in case-fatality rates among diabetic patients with myocardial infarction.Diabetes Care. 1991; 14: 903-908Crossref PubMed Scopus (30) Google Scholar Additional studies found little impact of diabetes on short-term post-AMI mortality in either sex.6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar, 11Melchior T. Kober L. Madsen C.R. Seibaek M. Jensen G.V.H. Hildebrandt P. Torp-Pedersen C. Accelerating impact of diabetes mellitus on mortality in the years following an acute myocardial infarction.Eur Heart J. 1999; 20: 973-978Crossref PubMed Scopus (66) Google Scholar In 2 recent reports,12Vaccarino V. Horwitz R.I. Meehan T.P. Petrillo M.K. Radford M.J. Krumholz H.M. Sex differences in mortality after myocardial infarction evidence for a sex-age interaction.Arch Intern Med. 1998; 158: 2054-2062Crossref PubMed Scopus (170) Google Scholar, 13Vaccarino V. Parsons L. Every N.R. Barron H.V. Krumholz H.M. Sex-based differences in early mortality after myocardial infarction.N Engl J Med. 1999; 341: 217-225Crossref PubMed Scopus (1086) Google Scholar we demonstrated that the hospital case fatality rate of women relative to men varies with age: women have a higher mortality than men at younger but not at older ages, and the younger the age of the women, the higher their risk of death relative to men. A remarkable difference between younger female and male patients with AMI was a higher prevalence of diabetes in women. Adjustment for diabetes as well as for other coexisting illnesses, however, explained only a small portion of the higher risk of death for women. In these previous reports, we did not assess whether the sex-based mortality differences could be explained by a greater effect of diabetes in women than in men. In the present study, therefore, our specific purpose was to determine whether the higher hospital mortality of younger female AMI patients compared with men can be explained by a greater adverse effect of diabetes in women (i.e., whether a higher mortality in women compared with men would be mostly observed among patients with diabetes). The National Registry of Myocardial Infarction 2 includes 772,586 patients admitted consecutively with an AMI to 1,674 US hospitals between June 1, 1994, and March 31, 1998.14Barron H.V. Michaels A.D. Maynard C. Every N.R. Use of angiotensin-converting enzyme inhibitors at discharge in patients with acute myocardial infarction in the United States Data from the National registry of Myocardial Infarction 2.J Am Coll Cardiol. 1998; 32: 360-367Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar Case ascertainment and clinical data were validated by comparison with the Cooperative Cardiovascular Project and found to be excellent.15Every N.R. Fredrick P.D. Robinson M. Sugarman J. Bowlby L. Barron H.V. A comparison of the National Registry of Myocardial Infarction 2 with the Cooperative Cardiovascular Project.J Am Coll Cardiol. 1999; 33: 1886-1894Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar Included in the current analysis were 160,773 patients aged 30 to 69 years with no prior history of myocardial infarction, who were not transferred from or to other acute care institutions during their hospitalization. Older patients were excluded because the purpose of the analysis was to explain sex differences in mortality at a younger age, and because diabetes is less important as a prognostic factor among older AMI patients of either sex.6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar, 10Cooper R.S. Pacold I.V. Ford E.S. Age-related differences in case-fatality rates among diabetic patients with myocardial infarction.Diabetes Care. 1991; 14: 903-908Crossref PubMed Scopus (30) Google Scholar Information on study variables was abstracted from the medical records at each hospital as previously described.13Vaccarino V. Parsons L. Every N.R. Barron H.V. Krumholz H.M. Sex-based differences in early mortality after myocardial infarction.N Engl J Med. 1999; 341: 217-225Crossref PubMed Scopus (1086) Google Scholar Patients were considered diabetic if they had a history of the disease as stated in the medical records. Information on type of diabetes, severity of diabetes, or current antidiabetic treatments was not available. Demographic factors, medical history, admission clinical characteristics, hospital complications, and treatments were compared between women and men according to presence or absence of diabetes. To assess the impact of diabetes on sex differences in mortality and the effect of adjusting for covariables, a logistic regression analysis was conducted. The odds ratio (OR) of hospital mortality for women compared with men and its 95% confidence interval (CI) were calculated according to the presence or absence of diabetes by including the interaction between sex and diabetes in the models before and after adjusting for age and other variables. Women overall were older than men, but this was mostly true among patients without diabetes (Table I). Among diabetics, sex difference in age was small. Compared with men, women were more likely to have coexisting illnesses such as congestive heart failure, hypertension, and previous stroke, and to have lower blood pressure and higher pulse rate on admission. These differences were more marked in the group without diabetes, suggesting that the older age of the women could play a role. On the other hand, despite similar rates of a previous diagnosis of angina, in both groups women were less likely than men to have had a previous revascularization procedure (coronary bypass or coronary angioplasty). In both groups women were less likely than men to experience chest pain, to have ST-segment elevations on their initial electrocardiogram, to be treated with thrombolytic therapy and β blockers, and to experience congestive heart failure during the hospital course. The rate of other complications was similar between women and men.TABLE IComparison of Baseline Characteristics, Treatments, Complications, and Mortality Between Women and Men by Diabetes StatuslegendValues are expressed as percentages except where noted., legendPercentages do not always total 100 because of rounding. The p values are not reported because, given the large number of patients, assessing whether differences are statistically significant is not informative., legendAV = atrioventricular; ECG = electrocardiographic; MI = myocardial infarction; SVT = supraventricular tachycardia.No DiabetesDiabetesWomen (n = 32,570)Men (n = 88,894)Women (n = 16,363)Men (n = 22,946)Mean age (yr) ± SD58.4 ± 9.055.4 ± 9.259.9 ± 8.158.4 ± 8.3White race81.583.270.376.5Medical historyAngina pectoris10.110.114.513.4Congestive heart failure5.02.916.611.0Coronary bypass4.06.68.111.5Coronary angioplasty3.24.65.36.0Stroke4.42.99.47.4Systemic hypertension48.039.566.659.1Current smoker45.647.324.528.6Hypercholesterolemia30.530.030.429.2Admission clinical characteristicsKillip classI, no heart failure84.288.969.176.4II, heart failure9.97.218.114.6III, pulmonary edema3.92.510.67.6IV, cardiogenic shock1.81.22.01.2No chest pain on presentation23.217.135.128.7Systolic blood pressure (mm Hg)12076.881.080.281.8Pulse >100 beats/min21.214.933.326.9ECG findings on first electrocardiogramST elevation48.553.739.444.2Q wave11.013.511.012.8Nonspecific changes31.226.737.334.1Normal8.28.87.68.1Mean time to presentation (h) ± SD3.9 ± 4.73.6 ± 4.54.4 ± 4.94.1 ± 4.8Management in first 24 hoursThrombolytic therapy27.632.518.822.7Alternative reperfusion strategy14.017.69.711.7Aspirin81.286.674.780.5β blockers (intravenous)17.221.014.117.5β blockers (oral)37.942.333.037.8Angiotensin-converting enzyme inhibitors12.811.522.520.1Hospital complicationsHeart failure10.97.321.515.9Recurrent ischemia, angina, or MI12.211.411.810.6Second or third-degree AV block3.62.74.23.5SVT or ventricular fibrillation7.57.95.86.3Hospital mortality8.35.012.98.9legend Values are expressed as percentages except where noted.legend Percentages do not always total 100 because of rounding. The p values are not reported because, given the large number of patients, assessing whether differences are statistically significant is not informative.legend AV = atrioventricular; ECG = electrocardiographic; MI = myocardial infarction; SVT = supraventricular tachycardia. Open table in a new tab In the unadjusted data, women had a higher hospital mortality than men both among diabetic and nondiabetic patients (TABLE I, TABLE II), but the sex-based mortality difference was not more pronounced among diabetics. On the contrary, the sex-based mortality difference was higher in the group without (OR 1.70 for women compared with men) than with (OR 1.51 for women compared with men) diabetes, and diabetes was associated with a higher risk in men (OR 2.09 for diabetes) than in women (OR 1.85 for diabetes); p = 0.004 for interaction between sex and diabetes. Examination of separate age groups (30 to 49, 50 to 59, and 60 to 69 years) showed similar results, with a tendency for diabetes to be a stronger risk factor for mortality in men in the younger age groups (data not shown). To examine whether sex differences in age, coexisting illnesses, and treatments on admission played a role in the mortality differences according to sex, we added these variables sequentially to the model (Table II). Age adjustment resulted in similar estimates for the effect of sex on mortality among nondiabetics (OR 1.50 for women) and diabetics (OR 1.42 for women), and similar effect of diabetes on mortality in men (OR 1.73 for diabetics) and in women (OR 1.64 for diabetes), with a nonsignificant interaction between sex and diabetes (p = 0.21). These results indicate that the greater effect of female sex among nondiabetic patients and, conversely, the greater effect of diabetes in men in the unadjusted data were primarily due to the younger age of the nondiabetic men than patients in the other groups. Adjustment for comorbid conditions and, in a subsequent step, for treatments in the first 24 hours of admission (thrombolytic therapy or alternative reperfusion strategy, aspirin, β blockers, and angiotensin-converting enzyme inhibitors), resulted in further declines in the sex difference in mortality in both groups. In the final model, female sex was still associated with significantly greater odds of death both in nondiabetics (OR 1.32 for women) and in diabetics (OR 1.25 for women), whereas diabetes had a similar effect on mortality in men (OR 1.45 for diabetes) and in women (OR 1.38 for diabetes), p = 0.29 for the interaction between sex and diabetes.TABLE IIAssociation of Female Sex With Hospital Mortality According to Presence of Diabetes Before and After Adjusting for CovariablesUnadjustedAge AdjustedAdjusted for Age and Comorbidity∗Adjusted for age, race, insurance status, history of angina pectoris, congestive heart failure, coronary bypass surgery, coronary angioplasty, stroke, hypertension, hypercholesterolemia, current smoking status, hospital characteristics (number of beds and presence of cardiac catheterization and cardiac surgery facilities), and study year.Adjusted for Age, Comorbidity, and Treatments in First 24 Hours†Adjusted for all of the above plus thrombolytic therapy or alternative reperfusion strategy, aspirin, β blockers, and angiotensin-converting enzyme inhibitors administration in the first 24 hours of admission.OR (women vs men)95% CIOR (women vs men)95% CIOR (women vs men)95% CIOR (women vs men)95% CINo Diabetes1.701.62–1.791.501.42–1.571.491.41–1.571.321.25–1.39Diabetes1.511.42–1.611.421.33–1.511.361.27–1.461.251.17–1.35∗ Adjusted for age, race, insurance status, history of angina pectoris, congestive heart failure, coronary bypass surgery, coronary angioplasty, stroke, hypertension, hypercholesterolemia, current smoking status, hospital characteristics (number of beds and presence of cardiac catheterization and cardiac surgery facilities), and study year.† Adjusted for all of the above plus thrombolytic therapy or alternative reperfusion strategy, aspirin, β blockers, and angiotensin-converting enzyme inhibitors administration in the first 24 hours of admission. Open table in a new tab Our results did not confirm our hypothesis that the higher hospital mortality rate after AMI in young and middle-aged women compared with their male counterparts may be explained by a more adverse effect of diabetes in women. In the unadjusted results, diabetes was a stronger risk factor for mortality in men than in women. This gender-based difference in the effect of diabetes was mostly explained by the younger age of the men without diabetes. Our study confirms a number of previous investigations that have also failed to find a higher impact of diabetes on short-term mortality after AMI in women than in men.6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar, 8Behar S. Boyko V. Reicher-Reiss H. Goldbourt U. Ten-year survival after acute myocardial infarction comparison of patients with and without diabetes.Am Heart J. 1997; 133: 290-296Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 10Cooper R.S. Pacold I.V. Ford E.S. Age-related differences in case-fatality rates among diabetic patients with myocardial infarction.Diabetes Care. 1991; 14: 903-908Crossref PubMed Scopus (30) Google Scholar Therefore, other explanations should be sought for the higher short-term post-AMI mortality of young and middle-aged women versus men. Our analysis only addressed hospital mortality. Previous publications have produced fairly consistent results of a greater impact of diabetes in women when long-term mortality is examined,5Abbott R.D. Donahue R.P. Kannel W.B. Wilson P.W.F. The impact of diabetes on survival following myocardial infarction in men vs women.JAMA. 1988; 260: 3456-3460Crossref PubMed Scopus (419) Google Scholar, 6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar, 7Miettinen H. Lehto S. Salomaa V. Mahonen M. Niemela M. Haffner S.M. Pyorala K. Tuomilehto J. Impact of diabetes on mortality after the first myocardial infarction.Diabetes Care. 1998; 21: 69-75Crossref PubMed Scopus (616) Google Scholar, 8Behar S. Boyko V. Reicher-Reiss H. Goldbourt U. Ten-year survival after acute myocardial infarction comparison of patients with and without diabetes.Am Heart J. 1997; 133: 290-296Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar which has been attributed to a higher incidence of severe congestive heart failure in diabetic women5Abbott R.D. Donahue R.P. Kannel W.B. Wilson P.W.F. The impact of diabetes on survival following myocardial infarction in men vs women.JAMA. 1988; 260: 3456-3460Crossref PubMed Scopus (419) Google Scholar, 16Savage M.P. Krolewski A.S. Kenien G.G. Lebeis M.P. Christlieb A.R. Lewis S.M. Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor.Am J Cardiol. 1988; 62: 665-669Abstract Full Text PDF PubMed Scopus (131) Google Scholar possibly through a mitigation of the protective effects of estrogen on cardiovascular function.17Sowers J. Diabetes mellitus and cardiovascular disease in women.Arch Intern Med. 1998; 158: 617-621Crossref PubMed Scopus (229) Google Scholar Therefore, if a greater mortality risk of young and middle-aged women compared with men persists in the long term after AMI, a differential impact of diabetes may well play a role. Because the effect of diabetes is stronger on long-term mortality than immediately after myocardial infarction,11Melchior T. Kober L. Madsen C.R. Seibaek M. Jensen G.V.H. Hildebrandt P. Torp-Pedersen C. Accelerating impact of diabetes mellitus on mortality in the years following an acute myocardial infarction.Eur Heart J. 1999; 20: 973-978Crossref PubMed Scopus (66) Google Scholar sex differences in this time-dependent effect also need to be examined. A definite diagnosis of diabetes based on standard criteria was not available in this study, and we were also unable to distinguish between insulin-dependent and non–insulin-dependent diabetes. Likewise, information on the severity of diabetes was not available. Our definition of diabetes was based on medical records as noted by the attending physician. Although this approach is consistent with most previous studies of AMI samples, it may have caused misclassification of diabetes, mainly due to underdiagnosis of diabetes.6Donahue R.P. Goldberg R.J. Chen Z. Gore J.M. Alpert J.S. The influence of sex and diabetes mellitus on survival following acute myocardial infarction a community-wide perspective.J Clin Epidemiol. 1992; 46: 245-252Abstract Full Text PDF Scopus (80) Google Scholar However, although the rate of undiagnosed diabetes is considerable in community settings,18Harris M.I. Flegal K.M. Cowie C.C. Eberhardt M.S. Goldstein D.E. Little R.R. Wiedmeyer H.M. Byrd-Holt D.D. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U. S. adults. The Third National Health and Nutrition Examination Survey. 1988–1994.Diabetes Care. 1998; 21: 518-524Crossref PubMed Scopus (2473) Google Scholar among AMI patients it is much less: from as low as 0.5% in some studies9Chun B.Y. Dobson A.J. Heller R.F. The impact of diabetes on survival among patients with first myocardial infarction.Diabetes Care. 1997; 20: 704-708Crossref PubMed Scopus (92) Google Scholar to about 5% in other studies.19Oswald G.A. Corcoran S. Prevalence and risks of hyperglycemia and undiagnosed diabetes in patients with acute myocardial infarction.Lancet. 1984; 1: 1264-1267Abstract PubMed Scopus (150) Google Scholar, 20Madsen J.K. Haunsoe S. Helquist S. Hommel E. Malthe I. Pedersen N.T. Sengelov H. Ronneow-Jessen D. Telmer S. Parving H.H. Prevalence of hyperglycemia and undiagnosed diabetes mellitus in patients with acute myocardial infarction.Acta Med Scand. 1986; 220: 329-332Crossref PubMed Scopus (34) Google Scholar Such misclassification appears to be similar in men and women.19Oswald G.A. Corcoran S. Prevalence and risks of hyperglycemia and undiagnosed diabetes in patients with acute myocardial infarction.Lancet. 1984; 1: 1264-1267Abstract PubMed Scopus (150) Google Scholar Therefore, if an underestimation of diabetes prevalence occurred in our study, this is likely to be small and to result in underestimation of the effect of diabetes in both sexes without substantially affecting our results. In conclusion, young and middle-aged women who have AMI have a higher hospital mortality than men irrespective of diabetes status. Effect modification due to diabetes status does not appear to play a role in the higher short-term mortality risk of younger women compared with men.