D iabetes is associated with an adverse prognosis after ST-segment elevation myocardial infarction (STEMI).1 Knowledge regarding the cause of this increased mortality is limited, however. Furthermore, published data on long-term clinical outcomes in diabetic patients after STEMI are mainly based on studies in which only a portion of the population received reperfusion therapy.2 To better understand the unfavorable prognosis of diabetic patients after STEMI, we investigated long-term mortality among patients with STEMI who were treated with reperfusion therapy as part of the Zwolle study.
Materials and methods
The study sample has been described previously.3 Baseline characteristics, clinical data, angiographic data, discharge medication, and outcome were recorded prospectively in a dedicated database. The study included patients who had no contraindications to thrombolytic therapy and had acute myocardial infarction (MI) symptoms for more than 30 minutes with ST-segment elevation, as shown on electrocardiogram. Patients were randomly divided into two groups: One group received thrombolytic therapy with streptokinase (Kabikinase, Streptase), and the other group underwent percutaneous coronary intervention (PCI). Enzymatic infarct size was estimated by measurement of serial lactate dehydrogenase (LDH) activity. Between 4 and 10 days following treatment, equilibrium radionuclide ventriculography was used to measure left ventricular ejection fraction (LVEF). An LVEF below 40% was considered to be reduced. Patients were considered to have diabetes if their glucose level on hospital admission was 11.1 mmol/L or higher or if they had established diabetes and were taking insulin or oral hypoglycemic medication at the time of admission. Patients were followed up in September 2000. The end points of the study were the differences between diabetic and nondiabetic patients in total mortality and death due to heart failure.
SPSS 10.0 software was used for statistical analysis. Two-tailed Student’s t test was used to assess variations between group means. Hazard ratios were estimated by using Cox proportional hazards regression models. The Kaplan—Meier method was used to create cumulative survival curves. To analyze the differences between proportions, the chi-square test was employed.
The Zwolle study included 395 patients. Table 1 shows the baseline characteristics of the patients. Diabetic patients had multivessel disease (MVD) more frequently, were more frequently women, and tended to be older.
Infarct size. Compared with nondiabetic patients, those with diabetes more often had an LVEF below 40% (27% versus 15%; odds ratio [OR], 2.1; 95% confidence interval [CI], 1.3—3.9; P = .02). The mean LVEF was also lower in these patients (44 ± 12% versus 48 ± 11%; P = .01). Enzymatic infarct size was significantly greater in patients with diabetes compared with patients without diabetes (1,435 ± 1,372 U/L versus 1,037 ± 847 U/L; P = .003; Table 1).
Total and cause-specific mortality. In total, 105 patients died (27%) during follow-up (mean, 8 ± 2 years). In the diabetes group, 32 patients (43%) died versus 73 patients (23%) in the nondiabetes group (OR, 2.6; 95% CI, 1.5—4.4; P < .001). In particular, death due to heart failure was higher in patients with diabetes compared with those without diabetes (14% versus 5%; OR, 3.0; 95% CI, 1.3–6.9; P = .01). Survival curves with regard to mortality due to heart failure are shown in the Figure. Sudden death was not significantly higher in patients with diabetes compared with those without diabetes (11% versus 9%; OR, 1.3; 95% CI, 0.6–2.9). Table 2 shows total and cause-specific mortality.
Multivariate analysis. Diabetes was shown to be an independent risk factor for total long-term mortality (OR, 2.2; 95% CI, 1.4—3.4; P < .001) and death due to heart failure (OR, 2.7; 95% CI, 1.2–6.2; P = .02) as shown on multivariate analysis (Table 3). When reduced LVEF was also included in the analysis, diabetes remained associated with long-term mortality (OR, 2.0; 95%
CI, 1.3—3.3; P = .003).
Compared with nondiabetic patients, STEMI patients with diabetes had a larger enzymatic infarct size, lower ejection fraction, and higher long-term mortality, even though they were treated with reperfusion therapy. Heart failure was the cause of the increased mortality. Diabetes was an independent predictor of both all-cause mortality and death due to heart failure.
Patients with diabetes were older, were more often women, and had more extensive coronary artery disease. After adjustment for differences in baseline characteristics, diabetes remained an independent predictor of long-term mortality. Even after inclusion of reduced LVEF in the multivariate analysis, diabetes remained an independent predictor of long-term mortality. The presence of a procoagulant state, a greater incidence of comorbid conditions, and undesirable lipid levels could play a role in the increased mortality.
The higher prevalence of reduced LVEF in patients with diabetes could be attributed in part to the greater incidence of MVD in these patients.4 Preexisting reduced LVEF, as a result of diabetic cardiomyopathy, may likewise play a role. Other factors may also be important, however. Metabolic derangement, including the utilization of excess free fatty acids, negatively influences myocardial function during myocardial ischemia and causes myocardial cells to be more susceptible
to reperfusion and ischemic damage.5 Moreover, myocardial preconditioning is absent or reduced in patients with diabetes.6
Interestingly, the increased mortality in patients with diabetes was mainly due to heart failure. This is probably because of the reduced LVEF in diabetic patients. However, although heart failure is clearly associated with reduced LVEF, diabetic patients seem to be particularly prone to associated clinical symptoms.7 Diastolic dysfunction may be important in these patients.8 It is possible that the combination of preexisting diastolic dysfunction with newly reduced systolic function makes diabetic patients more susceptible to the development of clinical heart failure. Disturbed myocardial substrate utilization accompanying impaired glucose metabolism also negatively influences myocardial function. The existence of a specific diabetic cardiomyopathy, which is believed to be caused by a number of different actions, including increased fibrosis, also makes heart failure more likely.9
We showed that mortality in patients with diabetes is still high, despite adequate reperfusion therapy. Additional interventions are therefore needed to improve the prognosis of diabetic patients after MI. Careful control of glucose metabolism during MI in patients with diabetes seems to reduce mortality. Patients with diabetes and STEMI enrolled in the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study who received insulin-glucose infusions followed by multiple insulin injections had a decreased death rate.10 The relative benefit of using angiotensin-converting enzyme inhibitors and beta-adrenergic blocking agents for the treatment of heart failure is equal in diabetic patients compared with nondiabetic patients. An effort should therefore be made to improve the present pharmacologic treatment of patients with diabetes after MI.11
Patients with depressed left ventricular function due to recurrent ischemic events may potentially benefit from aggressive revascularization therapy.12 Evidence suggests that coronary artery bypass grafting is preferable to PCI in diabetic patients with MVD, particularly when arterial bypass is used.13 The use of drug-eluting stents may help to reduce the greater risk of restenosis following PCI in diabetic patients.14 There is also a potential benefit to the use of implantable automatic cardiac defibrillators in patients with reduced LVEF after acute MI. The favorable effects of this intervention in patients with diabetes are probably small, however, because there was no increase in sudden death in diabetic patients in our study. Diabetic patients should receive long-term comprehensive treatment designed to address all risk factors and not just receive therapy when an acute coronary event occurs.15
We were not able to explore the effect of diastolic dysfunction on clinical heart failure in our patients because no specific diastolic parameters were measured. Also, no data were available regarding cardiac dysfunction before the index infarction because patients were derived from a normal community population.
Patients with diabetes have an adverse prognosis after MI, even when they receive reperfusion treatment. The increase in long-term mortality after acute MI in patients with diabetes is mainly due to an increase in death caused by heart failure.