a Department of Cardiology, Karolinska University Hospital Solna, Stockholm, Sweden
b Department of Medicine, Västerås Hospital, Sweden
c Department of Epidemiology and Biostatistics, Karolinska Institute, 171 76 Stockholm, Sweden
Received September 3, 2004; revised September 19, 2004; accepted September 28, 2004 * Corresponding author. Tel.: +46 8 517 70461; fax: +46 8 31 10 44 (E-mail: malgorzata.bartnik{at}medks.ki.se).
See page 1969 for the editorial comment on this article (doi:10.1016/j.ehj.2004.10.003)
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Abstract |
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METHODS AND RESULTS: Patients (n=168; age 63.5±9.3 years) with MI, no previous DM and admission blood glucose <11.0 mmol/l were followed for major cardiovascular events defined as the composite of cardiovascular death, non-fatal MI, non-fatal stroke or severe heart failure (HF). According to an oral glucose tolerance test (OGTT) before hospital discharge, 55 patients had normal and 113 abnormal glucose tolerance (GT). During the follow-up of median 34 months there were eight cardiovascular deaths, 15 patients had a recurrent MI, six had a stroke and ten severe HF. All patients who died from cardiovascular causes had abnormal GT. The composite cardiovascular event occurred in 31 (18%) patients. The probability of remaining free from cardiovascular events was significantly higher in patients with normal than abnormal GT (p=0.002). Together with previous MI, abnormal GT was the strongest predictor of future cardiovascular events (hazard ratio 4.18; CI 1.26-13.84; p=0.019).
CONCLUSIONS: Abnormal glucose tolerance is a strong risk factor for future cardiovascular events after myocardial infarction. Since it is common and possible to detect even during the hospital phase it may be a target for novel secondary preventive efforts.
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Introduction |
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The GAMI (Glucose tolerance in Patients with Acute Myocardial Infarction) study verified the primary hypothesis that impaired glucose metabolism is common in patients with myocardial infarction and possible to detect already during the early course of the disease.10 This report deals with the secondary objective of the GAMI study, which was to relate long-term outcome to the newly diagnosed glucometabolic state of these patients.
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Patients and methods |
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The study complies with the Declaration of Helsinki. The Ethics Committee of the Karolinska Institute approved the study protocol and all recruited patients gave their written informed consent.
Patients
Demographic data and clinical characteristics at admission were recorded according to the study protocol.10 Glucose metabolism was assessed by means of fasting capillary blood glucose measured daily during the hospital stay and a standard oral glucose tolerance test (OGTT; 75g glucose in 200 ml water) during stable conditions before hospital discharge (day 4 or 5).11 Patients were classified, as defined below, into one of the following categories: diabetes mellitus, impaired glucose tolerance or normal glucose tolerance. Compared to previous reports, four further patients were classified. Two developed overt hyperglycaemia during hospitalization and two were previously reported as missing by logistic reasons.10
Assays
Admission blood glucose was measured with a photometer immediately after sampling (HemoCue AB, Ängelholm, Sweden). Glycosylated hemoglobin A1c (HbA1c) was analysed by high pressure liquid chromatography (HPLC) from blood applied to filter paper (normal values <5.3%; Boehringer Mannheim Scandinavian AB, Bromma, Sweden).12 Venous blood was sampled fasting on the first morning following admission (within 24 hours of admission) and during the OGTT (at 0 and 120min) before discharge. Plasma obtained by centrifugation was stored at 70 °C until assayed.
Plasma lipids, total cholesterol, high-density lipoprotein cholesterol (HDL-cholesterol) and triglycerides, were measured by standard methods and low-density lipoprotein cholesterol (LDL-cholesterol) was calculated according to Friedewald's formula. Apolipoprotein B was analysed by turbidometry with specific antibodies and Syncron LX Systems APO Calibrator (Beckman Coulter Fullerton, CA, USA). Lipoprotein(a) (Lp(a)) was analysed with the TintElize Lp(a) kit (Biopool International, Umeå, Sweden). Free fatty acids (FFA) were determined with an enzymatic colorimetric method from Wako Chemicals GmbH (Neuss, Germany).
Concentrations of insulin and intact pro-insulin were quantified with immunoassays from DAKO Diagnostics Ltd. (Cambridgeshire, UK). C-reactive protein (hs-CRP) was determined by an ultra sensitive latex-enhanced immunoassay (BN II instrument, Dade Boehring, Marburg GmbH, Germany). Plasma PAI-1 activity was measured with Chromolize PAI-1 kits (Biopool International, Umeå, Sweden). Urine concentration of albumin was analysed on Image Immunochemistry systems (Beckman Instrument, Fullerton, CA, USA) and creatinine with use of a Victor 950 (Johnson and Johnson Clinical Diagnostics, Rochester, NY, USA).
Definitions
Myocardial infarction was diagnosed according to the joint recommendations of the ESC and ACC.13 Myocardial infarction was diagnosed if markers of myocardial ischaemia exceeded the upper reference limit on two occasions (troponin T>0.05 g/l or CK-MB >10 μg/l) in the presence of typical symptoms (chest pain >15 min, pulmonary oedema in the absence of valvular heart disease, cardiogenic shock, ventricular tachycardia or ventricular fibrillation) or new Q-waves in at least two of the 12 standard an ECG leads, or ECG indicating acute ischaemia (ST-segment elevation, ST-depression or T-wave inversion).
History of hypertension was recorded if treated prior to enrolment.
Dyslipidaemia was defined in case of HDL-C <0.9 mmol/l in men (<1.0 in women) and/or triglycerides 1.7 mmol/l.11 Micro-albuminuria was recognized based on the albumin: creatinine ratio (ACR) analysed in the morning urine sampled before discharge according to the WHO recommendations (ACR> 30mg/g).11
The glucometabolic state was classified based on the WHO criteria for capillary whole blood. Normal glucose tolerance (NGT) was recognized as a fasting blood glucose <6.1 mmol/l and 2-h post-load glucose <7.8 mmol/l. Impaired glucose tolerance (IGT) was defined as fasting blood glucose <6.1 mmol/l and 2-h post-load glucose of 7.811.0 mmol/l and diabetes mellitus (DM) as a fasting blood glucose >6.0 mmol/l or a 2-h post-load glucose >11.0 mmol/l.11 The term abnormal glucose tolerance is used to describe the presence of newly detected type 2 diabetes mellitus or IGT.
All patients were treated according to the clinical presentation following the established national and international guidelines without any attention to the glucose tolerance assessed immediately before hospital discharge.14
Outcome measures
Cardiovascular death was defined as death from myocardial infarction, stroke and sudden death without any obvious reason.
A non-fatal re-infarction was defined as a non-fatal myocardial infarction occurring later than 72 h after the index infarction.
Stroke was defined according to the WHO criteria as a neurological deficit observed by a physician and persisting >24 hours without any other disease explaining the symptoms.15 Severe heart failure was recognized when causing hospital admission including intensified, or additional treatment.
A composite outcome was defined as major cardiovascular event representing the first occurrence of stroke, re-infarction, severe heart failure or cardiovascular death.
Statistical analysis
Continuous variables are presented as median (lower and upper quartile) and categorical variables as counts and proportions (%). In the statistical analyses regarding the relation of various clinical and biochemical parameters to the occurrence of outcome events, only patients whose glucometabolic state was classified (n=168), were included. The 13 unclassified patients are described on an individual basis (Table 2). Differences of baseline characteristics between patients grouped by glucose tolerance status (normal and abnormal) were compared by the 2 test, two-tailed Fisher's exact test or Wilcoxon rank-sum test using STATISTICA version 6.1 (Tables 1, 3). KaplanMeier curves were computed for the composite endpoint of major cardiovascular events and Gehan's generalized Wilcoxon test was used to compare patients with normal and abnormal glucose tolerance.
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The following model selection strategy was used. Initially Cox regression models that contained each of the candidate predictors one at a time were fitted to determine which sole predictors had some importance (p value <0.2). Then all variables with a p value <0.2 (Table 5), together with current smoking and statin treatment at discharge, which are known to influence survival, were fitted together with abnormal glucose tolerance and forced into the model. All possible combinations of predictors were then fitted and the models were compared using the Akaike information criterion (AIC), which is minus two times the log likelihood plus a penalty function of two times the number of predictors in the model; the smaller the value of this criterion the better the model. The rationale behind this criterion is that if the only difference between two models is that a chance predictor has been included the values of the AIC for the two models will not differ much, but would rather tend to increase. Moreover, the AIC is an approximate measure of the prediction accuracy. The penalty function accounts for the fact that the same data is being used to fit the model and assess it through the likelihood. With this strategy, in contrast to a standard forward or backward selection, the problem that predictors are usually related to each other is avoided. We also avoided the problems with a high number of tests, only getting a single final model.1719 From a set of almost equal models, with respect to the AIC, the final model was chosen on medical grounds, only including predictors with a significant contribution (p<0.05) to avoid over-parametrization.
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Results |
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Patients with abnormal glucose tolerance were more likely to be older but did not differ regarding the prevalence of cardiovascular risk factors from their counterparts with normal glucose metabolism. Abnormal glucose tolerance was associated with higher plasma pro-insulin, hs-CRP and free fatty acids at discharge, as presented in Table 3.
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Discussion |
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An advantage with the current report is that evaluation of the glucometabolic state was achieved early and at the same time in all patients. According to our knowledge, the GAMI trial is the first to assess glucose metabolism by means of an OGTT within the first week in a contemporary population with myocardial infarction. As previously reported there was a very high correlation between OGTT performed before hospital discharge and three months thereafter opening a possibility for risk prediction already within the very early post-myocardial infarction period.20 Moreover, classification of glucometabolic state by means of OGTT has a particular value for the risk prediction of cardiovascular events in elderly patients.2123
The high incidence of cardiovascular events in the early post-infarction period as illustrated by rapidly diverging Kaplan-Meier curves resembles the impact of impaired fasting glucose on all-cause mortality reported in a large registry of patients with coronary artery disease.24
A substantial proportion of cardiovascular events would not be identified if classification were conducted several weeks after hospital discharge as emphasised by the LAMBDA investigators.25
In agreement with other investigators, the difference between the incidence of cardiovascular events among patients with newly detected diabetes and less pronounced impairment of glucose tolerance was negligible.4,2224 The majority of events did, in fact, occur in patients with impaired glucose tolerance as also observed by the DECODE Investigators.4,23 This underlines the continuous risk with increasing blood glucose already apparent at levels considered fairly normal.3
The overall mortality of 11% is lower than the one year mortality of 13% described in non-diabetic patients followed by the Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA).26 However, the GAMI patients were younger and did not have admission hyperglycaemia >11 mmol/l or renal insufficiency and in addition they were able to participate in an OGTT on day 45. Thus, the patients studied in this report represent a relatively healthy subgroup of those admitted with myocardial infarction in every-day CCU settings. In this perspective the GAMI cohort is well suited to generate hypotheses to be confirmed in a larger setting.
In the multivariate analysis, glucometabolic status, together with a previous myocardial infarct and stroke, remained as the only risk predictors. Classical cardiovascular risk factors that contribute to the development and extent of arteriosclerosis did not critically influence the tempo in which subsequent major cardiovascular events occurred in contrast to the glucometabolic milieu. Abnormal glucose tolerance by its multiple interactions with inflammatory response, pro-oxidative stress and not the least pro-coagulatory properties may play an important role for promoting adverse events.9,27 In this context, the completeness of follow-up and the extended metabolic characterisation, including hs-CRP, PAI-1 activity, pro-insulin, insulin levels and plasma free fatty acids can be accounted for additional advantage of this study.
Reperfusion therapy, which was less commonly applied in patients who experienced major cardiovascular events, together with age and use of statins, did not improve the Cox multiple regression model. In contrast, abnormal glucose tolerance was associated with four times higher risk for the composite of cardiovascular death, re-infarction, stroke or severe heart failure during a median follow-up time of 34 months.
The important role of fasting glycaemia and the unexpected strength of its impact on the mortality rate after percutaneous coronary interventions has very recently been proven and discussed by Muhlestein et al., who found the prevalence of abnormally elevated fasting glucose of 61% in patients with CAD undergoing PCI procedures.28
Study limitations
The GAMI patient population is fairly small. Thus despite a seemingly convincing message, this observation needs confirmation in a larger study. The Euro Heart survey on diabetes and the heart29 offers such opportunity. Preliminary one-year follow-up data in 2000 of the almost 5000 included patients in total showed an increased mortality among patients with newly detected pertubations in the glucose metabolism (Rydén et al., unpublished data on file).
The rigorous protocol applied in the GAMI study resulted in a loss of 13 patients from further analysis. Several of these patients would probably have had abnormal glucose tolerance if tested. This assumption is supported by their rather high average age, fairly high BMI and that several of them had a history of previous myocardial infarction, heart failure or hypertension (Table 2). Glucometabolic perturbations were in fact subsequently detected in three of them and 5 out of 13 had elevated HbA1c. Although this loss of patients decreased the statistical power, it was perceived appropriate to limit observations to patients in whom the metabolic status was precisely characterised rather than applying an 'intention to treat' principle as in trials addressing treatment modalities.
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Clinical implications |
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Acknowledgments |
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Footnotes |
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References |
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