European Heart Journal Advance Access originally published online on February 23, 2005
European Heart Journal
2005 26(7):650-661; doi:10.1093/eurheartj/ehi199
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Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity
1Department of Cardiology, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden
2Nordic School of Public Health, Göteborg, Sweden
3Department of Endocrinology, Aker University Hospital, Oslo, Norway
4Department of Medicine, Erasmus MC, Rotterdam, The Netherlands
5Department of Medicine, Rogaland Hospital, Stavanger, Norway
6Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
7Department of Endocrinology, Glasgow Royal Infirmary, Glasgow, UK
8Department of Medicine, Sahlgrenska University Hospital, Göteborg, Sweden
9Department of Cardiology and Endocrinology, Frederiksberg Hospital, Frederiksberg, Denmark
10Department of Medicine, Royal Devon and Exeter Hospital, Exeter, UK
11Department of Medicine, Kuopio University Hospital, Kuopio, Finland
12Department of Medicine and Cardiology, Bispebjerg Hospital, Copenhagen, Denmark
13Department of Medicine, Umeå University Hospital, Umeå, Sweden
Received 31 December 2004; revised 1 February 2005; accepted 9 February 2005; online publish-ahead-of-print 23 February 2005.
* Corresponding author. Tel: +46 8 517 7121; fax: +46 8 31 10 44. E-mail address: lars.ryden{at}medks.ki.se
See page 639 for the editorial comment on this article (doi:10.1093/eurheartj/ehi232)
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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Aims Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. In the first DIGAMI study, an insulin-based glucose management improved survival. In DIGAMI 2, three treatment strategies were compared: group 1, acute insulin–glucose infusion followed by insulin-based long-term glucose control; group 2, insulin–glucose infusion followed by standard glucose control; and group 3, routine metabolic management according to local practice.
Methods and results DIGAMI 2 recruited 1253 patients (mean age 68 years; 67% males) with type 2 diabetes and suspected acute myocardial infarction randomly assigned to groups 1 (n=474), 2 (n=473), and 3 (n=306). The primary endpoint was all-cause mortality between groups 1 and 2, and a difference was hypothesized as the primary objective. The secondary objective was to compare total mortality between groups 2 and 3, whereas morbidity differences served as tertiary objectives. The median study duration was 2.1 (interquartile range 1.03–3.00) years. At randomization, HbA1c was 7.2, 7.3, and 7.3% in groups 1, 2, and 3, respectively, whereas blood glucose was 12.8, 12.5, and 12.9 mmol/L, respectively. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 (9.1 and 9.1 mmol/L) receiving insulin–glucose infusion than in group 3 (10.0 mmol/L). Long-term glucose-lowering treatment differed between groups with multidose insulin (
3 doses/day) given to 15 and 13% of patients in groups 2 and 3, respectively compared with 42% in group 1 at hospital discharge. By the end of follow-up, HbA1c did not differ significantly among groups 1–3 (
6.8%). The corresponding values for fasting blood glucose were 8.0, 8.3, and 8.6 mmol/L. Hence, the target fasting blood glucose for patients in group 1 of 5–7 mmol/L was never reached. The study mortality (groups 1–3 combined) was 18.4%. Mortality between groups 1 (23.4%) and 2 (22.6%; primary endpoint) did not differ significantly (HR 1.03; 95% CI 0.79–1.34; P=0.831), nor did mortality between groups 2 (22.6%) and 3 (19.3%; secondary endpoint) (HR 1.23; CI 0.89–1.69; P=0.203). There were no significant differences in morbidity expressed as non-fatal reinfarctions and strokes among the three groups.
Conclusion DIGAMI 2 did not support the fact that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction when compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control seems to be an important part of their management.
Key Words: Myocardial infarction • Diabetes mellitus • Mortality • Morbidity • Insulin • Metabolic control
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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Type 2 diabetes is an important cause of cardiovascular morbidity and mortality accounting for >20% of the total number of patients admitted for suspected myocardial infarction. Patients with diabetes have a two-fold increase in hospital mortality when compared with those without diabetes. Long-term follow-up reveals a continuously increasing excess mortality, mostly due to fatal re-infarctions and congestive heart failure.1–3 The difference in mortality and morbidity between patients with and without diabetes has remained despite improved therapeutic modalities that have resulted in a decline in the overall morbidity and mortality following acute myocardial infarction.4–6
Factors of possible importance for the poor prognosis among diabetic patients with acute myocardial infarction may act before, during, or after an event. As recently reviewed, these include diffuse coronary atherosclerosis, a possible diabetic cardiomyopathy, autonomic neuropathy with impaired pain perception and increased heart rate, an increased propensity to thrombus formation, and an impaired fibrinolytic function. Some of these factors are related to the metabolic control and are favourably influenced by insulin.7 Acute myocardial infarction causes a dramatic increase in adrenergic tone, which stimulates lipolysis, thereby increasing the levels of free fatty acids. Several hormonal mechanisms contribute to a decrease in insulin sensitivity and glucose utilization during acute myocardial ischaemia. This is particularly evident in the diabetic patient, who already has a diminished capability to secrete insulin and to use glucose for production of energy rich phosphates. Free fatty acids are harmful to the myocardium through several mechanisms. In addition, an excessive oxidation of free fatty acids may possibly jeopardize non-ischaemic parts of the myocardium.8
In the DIGAMI trial, patients with diabetes and acute myocardial infarction were randomly assigned to a control group or to receive intense insulin treatment initiated by insulin–glucose infusion during the first 24 h after myocardial infarction. The 1 year mortality was reduced by 30% in the intensively treated group. After an average of 3.4 years, there was an 11% absolute mortality reduction among these patients.9,10 As total mortality in the first DIGAMI study was lower than expected, there was little statistical power to detect reasons for this mortality reduction. Moreover, the study could not answer the question of whether the beneficial effects related to the acute insulin–glucose infusion or to the continuous insulin-based metabolic control or both.
The DIGAMI 2 trial was planned and conducted to further explore the possible benefits of an insulin-based management of diabetic patients with myocardial infarction. The hypothesis behind the study was that early and continued insulin-based metabolic control is a key to mortality reduction.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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Design
DIGAMI 2 was a multicentre, prospective randomized, open trial with blinded evaluation comparing three different management strategies in patients with type 2 diabetes and acute myocardial infarction. The management protocols were (i) a 24 h insulin–glucose infusion followed by a subcutaneous insulin-based long-term glucose control (group 1), (ii) a 24 h insulin–glucose infusion followed by standard glucose control (group 2), and (iii) routine metabolic management according to local practice (group 3). The study was performed in 44 centres in Sweden, Finland, Norway, Denmark, The Netherlands, and the UK (see Appendix). Patient recruitment started in January 1998 and ended in May 2003. Follow-up for mortality and morbidity was concluded in December 2003.
The primary objective of DIGAMI 2 was to compare total mortality between treatment groups 1 and 2 during the time of follow-up. A secondary objective was to compare the total mortality between groups 2 and 3, and a tertiary objective to compare morbidity, such as non-fatal reinfarction, congestive heart failure, and stroke, among the three groups.
Patients
Patients with established type 2 diabetes or an admission blood glucose >11.0 mmol/L, admitted to participating coronary care units, were eligible for inclusion according to the following criteria: suspect acute myocardial infarction due to symptoms (chest pain >15 min during the preceding 24 h) and/or recent ECG signs (new Q-waves and/or ST-segment deviations in two or more leads). Exclusion criteria were inability to cope with insulin treatment or to receive information on the study; residence outside the hospital catchment area; participation in other studies, or previous participation in DIGAMI 2. The study conformed to good clinical practice guidelines and followed the recommendations of the Helsinki Declaration. Local ethics review boards approved the protocol. Written informed consent was obtained from all patients prior to enrolment.
Procedures
The computer-based randomization was centralized to the study coordinating office open 24 h/day (Karolinska Hospital, Stockholm, Sweden). An attempt for balanced randomization was performed directly after a patient had been evaluated for inclusion, given informed consent, and after baseline variables had been collected. Telecommunicated information about baseline variables were transferred into the computer and the subsequent randomization was based on an algorithm including important prognostic markers in the first DIGAMI trial9,10 as follows: age (>70 years vs. <70 years); previous myocardial infarction (yes/no); previous congestive heart failure (yes/no); ongoing treatment with digitalis (yes/no). The presence or absence of previous insulin treatment was also taken into account. Besides optimizing the likelihood to obtain comparable study groups, this procedure also improved the possibility to compare the outcome of DIGAMI 2 with predefined risk strata in the first DIGAMI trial.
Concomitant treatment
With regard to the open study design, the protocol stated that the use of concomitant treatment should be as uniform as possible and according to evidence-based international guidelines for acute myocardial infarction.11,12 In particular, it was emphasized that all patients without contraindications must be prescribed aspirin, thrombolytic agents, beta-blockers, lipid-lowering drugs, angiotensin-converting enzyme (ACE)-inhibitors, and revascularization procedures when appropriate.
Laboratory investigations
Random blood glucose was obtained as soon as possible after hospital admission. During the first 24 h, blood glucose was followed according to the infusion protocol in groups 1 and 2 and at the discretion of the attending physician in charge in group 3. Thereafter, fasting blood glucose was recorded daily until hospital discharge and at each follow-up visit. Data are reported as the locally analysed whole blood glucose in mmol/L. HbA1c was analysed by high-performance liquid chromatography in a core laboratory (Department of Laboratory Medicine, Malmö Hospital, Sweden) on capillary blood applied on filter paper with an upper normal limit of 5.3%. (Boerhringer Mannheim Scandinavian AB, Bromma, Sweden).13
Glucose-lowering treatment
In groups 1 and 2, glucose-lowering treatment was initiated with a glucose–insulin infusion as described in detail,9 with the objective to decrease blood glucose as fast as possible and keep it between 7 and 10 mmol/L. The infusion lasted until stable normoglycemia and at least for 24 h. In group 1, subcutaneous insulin was initiated at the cessation of the infusion. Insulin was given as short-acting insulin before meals and intermediate long-acting insulin in the evening. The treatment goal for patients in group 1 was a fasting blood glucose level of 5–7 mmol/L and a non-fasting level of <10 mmol/L. Apart from the initial insulin–glucose infusion given to patients in group 2, the glucose-lowering treatment in groups 2 and 3 was at the discretion of the responsible physician and according to local routines. The protocol did not define any target values in these groups. Hypoglycaemia was defined as a blood glucose <3.0 mmol/L and was recorded as with or without symptoms.
Follow-up
One week following hospital discharge, patients returned to a nurse-based outpatient clinic, in particular focusing on the treatment of diabetes. Outpatient visits to the responsible physician were scheduled after 3, 6, 9, and 12 months and thereafter every sixth month. All patients were followed for a minimum of 6 months, and the maximum time of follow-up was 3 years.
Events
Myocardial infarction was diagnosed according to the joint recommendations of the ESC and ACC.14 A reinfarction was defined as a new event >72 h from the index infarction. Stroke was defined as unequivocal signs of focal or global neurological deficit of sudden onset and a duration of >24 h that were judged to be of vascular origin. Deaths were verified with death certificates, hospital records, and explaining letters from the physicians in charge when asked for by the adjudication committee members and autopsy reports when available. Sudden cardiovascular deaths were those that occurred within 24 h following onset of symptoms and without any other obvious reason for the fatal outcome. Deaths were labelled as cardiovascular or non-cardiovascular, and those without any obvious non-cardiovascular cause were considered cardiovascular. Non-cardiovascular deaths, including malignancies, were adjudicated according the same principles as cardiovascular events. An independent committee comprising three experienced cardiologists adjudicated all events blindly and could, as indicated, ask for any type of information felt needed to ensure a correct classification of the events and the reasons for mortality.
Statistical methods
Sample size was based on the 2 year mortality of patients with type 2 diabetes in the control group of the first DIGAMI trial.10 The estimated 2 year mortality was close to 35% in group 3; however, adjusted to 30% to correct for time-trends in mortality. It was assumed that the mortality would be lowered to 17% in group 1 and 23% in group 2 corresponding to a mortality reduction of 25% between each of three treatment strategies. These assumptions would require a sample size of 1150 patients in groups 1 and 2 and 700 patients in group 3 for a two-tailed test with an alpha-value of 0.05 and a power of at least 85%. However, the power of a study with similar size as the present is only 50%.
The main analysis was performed by means of an un-adjusted Cox proportional hazards model on an intention to treat basis, while the proportional hazards assumption was not assessed. Adjustment for prognostic variables was applied in a secondary analysis. In an epidemiological analysis, background patient characteristics were entered together with updated values for HbA1c and fasting blood glucose as recorded during the time of follow-up in a Cox time-dependent analysis. For the primary hypothesis, a two-tailed statistical test was used at a 5% significance level, whereas a level of 1% was applied for all other comparisons. SAS version 8:12 was used for all statistical analyses.
The Steering Committee decided to stop patient recruitment on 21 May 2003, with the final follow-up scheduled for 15 December 2003. The reason was slow patient recruitment.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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Of 1253 patients, 474 (38%) were allocated to group 1, 473 (38%) to group 2, and 306 (24%) to group 3. The median study duration was 2.1 (interquartile range 1.03–3.00) years. No patient was lost to follow-up. At hospital discharge, 85, 84, and 84% of the patients in groups 1, 2, and 3 fulfilled the diagnosis of myocardial infarction, whereof 44, 42, and 46% were ST-elevation infarctions, respectively. Almost all remaining patients had coronary artery disease mostly presenting as unstable angina pectoris. Newly detected type 2 diabetes, defined as of a duration <1 year, was seen in 21, 24, and 23% of the patients in groups 1, 2, and 3, respectively. Baseline characteristics and pertinent biochemical and clinical data at the time of randomization and after 24 h are presented in Tables 1 and 2. The three groups were well balanced in most respects. However, there were significantly fewer previous myocardial infarctions and a trend towards less hypertension and heart failure in group 3. Around one-third had a previous myocardial infarction and the mean diabetes duration was 8 years. Thirty per cent was on some form of insulin treatment before randomization (Table 1). HbA1c (mean
7.3%) and blood glucose (12.7 mmol/L) did not differ among the groups at randomization. Blood glucose decreased significantly more in groups 1 and 2 during the first 24 h when compared with group 3, but the absolute difference between these groups and group 3 was only 0.9 mmol/L.
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Concomitant treatment during hospitalization and at discharge is outlined in Table 3. The use of evidence-based treatment was extensive in all groups. In particular, almost all patients eligible for acute revascularization received such treatment, mostly as thrombolysis. More than 80% of the patients were on beta-blockers at the time of hospital discharge. By the end of the study, somewhat >80% of the patients were on beta-blockers, 80% on aspirin, 65% on ACE-inhibitors/angiotensin receptor blockers (ARB), and 75% on lipid-lowering drugs, without any important differences among the three study groups.
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Glucose-lowering treatment and glucose control
The adherence to the infusion protocol was high in groups 1 (n=446; 94%) and 2 (n=444; 94%). Infusion of insulin–glucose was administered to significantly fewer patients in group 3 (n=44; 14%). At the time of hospital discharge, 84, 45, and 39% of the patients in groups 1, 2, and 3 were prescribed insulin at an average dose of 36 (22), 46 (30), and 57 (42) units, respectively. During follow-up, multidose insulin (three or more daily doses) was used in somewhat <50% of the patients in group 1 and in between 15 and 20% in groups 2 and 3, whereas
10% of the patients in group 1 and 15–20% of those in groups 2 and 3 did not receive any glucose-lowering drugs. Further details on long-term glucose-lowering treatment are presented in Table 4.
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Blood glucose <3 mmol/L with and without symptoms was more frequent during the initial 24 h in groups 1 (12.7%; symptomatic 27%) and 2 (9.6%; symptomatic 39%) than in group 3 (1.0%; symptomatic 33%).
Glucose control over time is presented in Figure 1A (blood glucose) and B (HbA1c). Apart from slightly but statistically significant lower blood glucose after 24 h in groups 1 and 2 compared with group 3, blood glucose and HbA1c did not differ significantly among any of the three groups when comparing the areas under the curve. The levels did not reach the targeted level between 5 and 7 mmol/L in group 1. The average increase in body weight was 4.7 kg in group 1 and 0.4 and 0.2 kg in groups 2 and 3, respectively. Average blood pressure at 2 years of follow-up was 137/77, 139/78, and 139/79 in groups 1, 2, and 3, respectively.
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Mortality-intention to treat
Overall, there were 277 deaths in the study (21.3%). Mortality did not differ significantly among the three groups as presented in Figure 2. After 2 years of follow-up, the Kaplan–Meier estimated mortality was 23.4% among patients in group 1 when compared with 21.2% in group 2 (HR=1.03; 95% CI=0.79–1.34; P=0.832). The corresponding proportion in group 3 was 17.9% (group 1 vs. 3: HR=1.26, CI=0.92–1.72; P=0.157). The adjusted HR for the slight imbalance in previous diseases between groups 1 and 3 was 1.19 (CI=0.86–1.64; P=0.29). Comparing groups 2 and 3, the HR=1.23 (CI=0.89–1.69; P=0.203). The following variables were selected for the adjusted endpoint analysis owing to their univariate relation with a P-value<0.20: myocardial infarction, chronic congestive heart failure, early ventricular fibrillation, and cardiogenic shock. Gender did not influence mortality. Specific causes of death are outlined in Table 5. Cardiovascular causes were most common without any significant differences among the groups, whereas a lower incidence of non-cardiovascular deaths in group 3 explained the trend towards a somewhat lower overall mortality in this group compared with groups 2 and 3. There was a slight difference in mortality from malignancies, with a higher incidence in group 1 (n=16) compared with group 2 (n=5) and group 3 (n=2; group 1 vs. 2, P=0.016; group 1 vs. 3, P=0.011). Eleven out of the 16 deaths due to malignancies in group 1 occurred during the first year of follow-up but none in groups 2 and 3, in which the first death due to malignant disease occurred after 1.2 and 1.9 years, respectively.
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Mortality–epidemiological analysis
Disregarding group allocation, entering patients characteristics, which in a univariate relation had a P-value<0.20 [updated mean HbA1c or updated mean blood glucose (depending on the analysis) together with age, gender, diabetes duration, previous heart failure, previous myocardial infarction, smoking, renal function expressed as s-creatinine at the time of randomization] into a multivariable analysis of mortality predictors (Figure 3). Updated blood glucose (HR=1.20 for 3 mmol/L; P<0.001) was a significant and independent predictor together with increasing age (HR=2.14 for 10 years; P<0.001), previous heart failure (HR=1.71; P<0.001), and elevated serum creatinin (HR=1.13 for 40 µmol/L; P<0.001). Applying this model introducing a 2% increase of updated HbA1c as a measure of glucose control revealed an HR of 1.19 (P=0.027).
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Morbidity
There was a trend towards fewer secondary events in groups 2 and 3 compared with group 1. However, this difference as presented in Figure 4 did not reach statistical significance for stroke (A) or myocardial reinfarction (B). Time to first major event (death, stroke, or reinfarction) has been outlined in Figure 5. The combined total event rate was high in the magnitude of 35–40%, but did not differ significantly among the three groups.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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The most important message from this investigation of three different treatment strategies for glucose control in patients with type 2 diabetes and acute myocardial infarction is that they were similar with regard to effects on long- or short-term mortality. Still, hyperglycaemia remained one of the most important prognostic predictors.
The DIGAMI 2 study, originally planned to recruit 3000 patients, was stopped prematurely owing to the slow patient recruitment rate. The slow recruitment may seem surprising in that diabetic patients comprise at least 20–25% of patients with myocardial infarction.3,15 An obvious solution would have been to increase the number of study centres and such attempts were repeatedly made. The nature of the study, a truly investigator-initiated trial, rendered it a low-budget trial despite generous research grants. A common reason for invited centres to decline participation was that the reimbursement offered was considered too low as it was based on calculations of actual resource consumption. This experience raises the question of whether time has come to discuss for which trials community-owned hospitals should be open, as well as reimbursement possibilities and principles in future clinical research, as has been acknowledged by the European Society of Cardiology.16
The slow recruitment rate and the fact that some centres recruited relatively few patients explained the slight imbalance among the three groups because the randomization algorithm was not applied until eight patients were included in an individual centre. This caused the patients in group 3 to be somewhat less sick than those in groups 2 and 3. Comparisons among groups were accordingly done both for crude and for adjusted HRs.
The Steering Committee repeatedly emphasized the importance of a strict adherence to the set targets for glucose control in study group 1. The protocol stated that patients in groups 2 and 3 should be treated at the discretion of the attending physician. The adherence to the glucose–insulin infusion prescribed for patients in groups 1 and 2 was high. This resulted in a better glucose control during the hospital period in these two groups than among those in group 3. However, although statistically significant, this difference was smaller than expected. Importantly, a total of 14% of patients in group 3 received insulin–glucose infusion, which was not advocated by the protocol, and as many as 41% had extra insulin injections. In contrast, the continued glucose-lowering treatment in group 1 was less effective than prescribed by the protocol. Many more patients in group 1 were on insulin than in groups 2 and 3, but <50% received insulin three or more times per day. It is therefore not surprising that long-term glucose control did not differ significantly among the three groups. It had been postulated that insulin-based treatment should be superior to glucose-lowering therapy by means of oral glucose-lowering agents. Thus, it was considered important to recruit enough patients to address this hypothesis. The reason for the somewhat vague conclusion in this respect is that the power of the study was decreased to 50% owing to the lower than planned number of recruited patients. Considering the very small differences in mortality among the three management strategies, it is still not reasonable to assume that a larger patient material would have disclosed any clinically meaningful differences between the different glucose-lowering treatments. Thus, the interpretation must be that there is no evidence to support a beneficial effect of insulin if sufficient amounts are not given to achieve a difference in glucose levels. The targeted level for glucose control in group 1, fasting blood glucose of 5–7 mmol/L, is in agreement with recent guidelines for prevention in patients with cardiovascular disease.17 The experience from DIGAMI 2, conducted by investigators with a special interest in the care of diabetic patients with acute myocardial infarction, indicates that this goal may be difficult to accomplish. Despite a strict protocol-defined strategy, in particular for patients in group 1, the target was not reached. Experience from the CODE study18 and registries19 does indeed support the finding that glucose control often is far from satisfactory albeit slowly improving.20 Accordingly, other management routines, including forced titration algorithms and improved pharmacological agents, are warranted for this large group of patients.
The outcome of DIGAMI 2 contrasts with the findings in the first DIGAMI trial, which concluded that an insulin–glucose infusion followed by insulin-based therapeutic regime reduced mortality in diabetic patients with acute myocardial infarction.9,10 Although the design of the second DIGAMI trial was based upon the first, there are differences. DIGAMI 1 recruited patients with any type of diabetes and required a blood glucose >11.0 mmol/L for eligibility, whereas the present patient population consisted of patients with type 2 diabetes without any blood glucose restrictions. This is demonstrated by the higher baseline blood glucose (15.5±4.5 vs. 12.8±4.5 mmol/L) in DIGAMI 1 when compared with DIGAMI 2. The reason for this is probably not only different eligibility criteria, but also an overall improved glycaemic control in diabetic patients.19 In addition, the initial decrease in blood glucose was more substantial in DIGAMI 1 (–5.8 mmol/L) than in DIGAMI 2 (–3.4 mmol/L), which may reflect that it was felt safer to lower a high glucose level than to normalize a lower value with an experienced risk of causing hypoglycaemia. Considering long-term glucose control, the insulin-based management strategy reduced HbA1c by 1.4% in the subgroup that benefited most in DIGAMI 1 which should be compared with 0.5% in all groups in DIGAMI 2. The overall long-term glucose control was better in the second than in the first DIGAMI trial, which may have had a favourable influence on the outcome in the latter. In DIGAMI 1, glucose control differed clearly between the insulin-treated and the control arms, but such difference was unfortunately not achieved in DIGAMI 2. The most likely reasons for this discrepancy are a better-than-expected blood glucose control in groups 2 and 3 in DIGAMI 2 and a less-than-ideal adherence to the use of insulin. The interpretation of DIGAMI 2 is that for a similar glycaemic control insulin treatment is not superior to the use of other therapeutic options as regards mortality outcome. DIGAMI 2 could not provide a firm answer to the important question of whether a glucose-lowering treatment towards normoglycaemia has a potential to further improve prognosis. The epidemiological analysis from DIGAMI 2 together with information from the study on patients in intensive care by Van den Berghe et al.21 strongly support the concept that a meticulous glucose control rather than insulin treatment or the insulin dose22 is the important factor. Thus, DIGAMI 2 supported by previous data suggests that type 2 diabetic patients should have an intensive glucose control after an acute myocardial infarction, but that this may be accomplished by alternative and perhaps more convenient treatment than insulin as long as glucose control is efficient.
The concept of initiating treatment with insulin infusion to rapidly attain a normalized blood glucose has support from the first DIGAMI trial and the study in patients in intensive care by Van den Berghe et al.21 DIGAMI 2 does not provide evidence against such therapy in patients with high admission blood glucose, but a pre-requisite seems to be that glucose is monitored carefully to achieve effective control. Other studies more directed towards metabolic support to the ischaemic myocardium are not comparable. None of them aimed for glucose control as a primary target. Indeed blood glucose increased in most of these studies during infusion of high concentrations of glucose–insulin–potassium.23,24
Mortality remains high among patients with diabetes and myocardial infarction as shown by recent registry studies, also reporting on a suboptimal use of established treatment modalities in these patients.3,25,26 In contrast, the overall mortality in DIGAMI 2 was considerably lower than the predicted 2-year mortality of 22–23%, which was based on the outcome of the first DIGAMI study with corrections for assumed time-trend in mortality owing to improved general management. A concern was a higher death rate by malignancies in group 1 than in groups 2 and 3. In group 1, most of these deaths occurred early, during the first year of follow-up, which is strong evidence against a true relation. The most likely explanation is unfavourable patient allocation in this particular respect, not covered for by our attempt to cause a balanced randomization. Moreover, the question concerning a possible relation between insulin and malignant diseases cannot be based on the few events in this trial but should, if of any further interest, be studied in large databases.
The actual 2 year mortality of 18.4% is, to the best of our knowledge, the lowest presented long-term mortality in a cohort of diabetic patients with myocardial infarction. This becomes even more evident when comparing the present 1-year mortality (
14%) with updated information on diabetic patients in the Swedish CCU registry (21%; data on file). Indeed, the 1-year mortality in DIGAMI 2 approaches 12% that for the non-diabetic registry patients. Needless to say, a selection bias hampers such comparisons, but the inclusion criteria in the DIGAMI 2 were wide and without age limits, whereas the registry does not include people above the age of 80 years. Although firm conclusions cannot be based on such comparisons, the DIGAMI 2 findings are promising. The most likely reasons for this beneficial outcome are a combination of improved glucose control and an extensive use of evidence-based treatment as prescribed by the protocol. Despite the fact that patients in study group 1 did not reach the protocol-outlined glucose levels, patients in all study groups alike had a better long-term glucose control than those in the first DIGAMI study. As regards concomitant treatment, thrombolysis or revascularization procedures were in principle offered to all patients with ST-elevation infarctions, and the use of beta-blockers, ACE-inhibitors, lipid-lowering drugs, and aspirin were indeed high. This assumption is supported by short-term data from the Munich registry report that intensification of multiple therapeutic strategies, including insulin infusions, resulted in a substantial reduction of in-hospital mortality comparable to the rates in non-diabetic patients.27
An important message from the DIGAMI 2 trial is that updated HbA1c and blood glucose were significant and independent mortality predictors together with the traditional risk factors age, heart failure, and elevated serum creatinin. Thus, an increase in blood glucose of 3 mmol/L or in HbA1c by 2% was associated with an increase in mortality by 20%. This underlines the importance of efforts finding pharmaceutical agents and management strategies that can effectively normalize blood glucose levels.
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Conclusions |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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The DIGAMI 2 trial did not support that an acutely introduced, long-term insulin treatment improves survival in type 2 diabetic patients following myocardial infarction compared with a conventional management at similar levels of glucose control or that insulin-based treatment lowers the number of non-fatal myocardial reinfarctions and strokes. However, an epidemiological analysis confirms that the glucose level is a strong, independent predictor of long-term mortality in this patient category, underlining that glucose control is an important part of their management.
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Acknowledgements |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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The study was supported by the Swedish Heart-Lung Foundation, AFA Insurance, The King Gustav V and Queen Victoria Foundation, the Swedish Medical Research Council, the Swedish Diabetes Association, and by unconditional research grants from Aventis Sweden and Novo Nordisk Denmark.
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Appendix: DIGAMI 2 Investigators |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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Steering committee
Lars Rydén (chairman), Karolinska Hospital, Stockholm; Klas Malmberg (principle investigator), Karolinska Hospital, Stockholm
From Sweden
Anders Hamsten, Karolinska Hospital, Stockholm; Suad Efendic, Karolinska Hospital, Stockholm; Anders Waldenström, Norrlands University Hospital, Umeå; Johan Herlitz, Sahlgrenska Hospital, Gothenburg; Hans Wedel, Nordic School for Public Health, Gothenburg
From Denmark
Per Hildebrandt, Frederiksbergs Hospital, Copenhagen; Christian Torp-Pedersen, Bispebjerg University Hospital, Copenhagen
From Finland
Markku Laakso, Kuopio University Hospital, Kuopio
From Norway
Kåre Birkeland, Aker Hospital, Oslo; Kenneth Dickstein, Stavanger University Hospital, Stavanger
From The Netherlands
Aart Bootsma, Erasmus MC, Rotterdam
From the UK
Kenneth Macleod, School of Postgraduate, Exeter; Miles Fisher, Glasgow Royal Infirmery, Glasgow
Publishing committee
Lars Rydén (chairman), Klas Malmberg (secretary), Anders Waldenström, Hans Wedel (biostatistician)
End point adjudication committee
Torbjörn Lundström, Mölndals Hospital, Sweden; Christer Wetterwik, Borås Hospital, Sweden; Seppo Lehto, Kuopio University Hospital, Finland
Safety monitoring committee
Ulf de Faire, Karolinska Hospital, Sweden; Jan Lanke (biostatistician), Lunds Univesity Hospital, Sweden; Kalevi Pyöräla, Kuopio University Hospital, Finland
Study centre
From Sweden
Karolinska University Hospital, Stockholm (central study office): physicians, L. Rydén, K. Malmberg, A. Norhammar; study nurses, secretaries, and BMI, R. Binisi, C. Edman, K. Höglund, M. Lidin, C. Hage, E. Wallgren
Borås Hospital: physicians, C. Wettervik, L. Andersson; study nurse, A. Prissberg
Sahlgrenska University Hospital, Göteborg: physician, J. Herlitz; study nurse, M. Sjölin
Kalmar Hospital: physician, F. Landgren; study nurse, E. Bjurling
Karlshamn Hospital: physician, S. Jénsen; study nurse, C. Olsson
Akademiska Hospital, Uppsala: physicians, G. Wikström, K. Eggers; study nurse, G. Alsjo
Västerås Hospital: physicians, Å. Tenertz, S. Bandh; study nurse, C. Andersson
Umeå University Hospital: physicians, P.A. Wiklund, K. Lindmark; study nurse, C. Sundholm
Eskilstuna Hospital: physician, A. Stjerna; study nurse, I. Söderberg
Örebro Hospital: physician, B. Ryttberg; study nurses, K. Björkman-Thofelt, M. Kvist
St Görans Hospital, Stockholm: physician, C. Hofman-Bang; study nurse, M. Sundström
Östra Hospital, Göteborg: physician, G. Dellborg; study nurses, A.M. Svensson, H. Svensson
Danderyd Hospital, Stockholm: physician, M. Björkstedt- Bennermo; study nurse, A. Broman
Nyköping Hospital: physician, V. Bergmark; study nurse, L. Strauss
Oskarshamn Hospital: physician, U. Mathisen; study nurse, A.M. Johansson
Södertälje Hospital: study nurse, A. Hedh
Lund University Hospital: physician, H. Öhlin; study nurse, G. Dahl
Uddevalla Hospital: study nurse, I. Johansson
Helsingborg Hospital: physicians, O. Fredholm, J. Forsblad; study nurse, K. Holmer
From Denmark
Frederiksbergs Hospital: physicians, I. Gustafsson, C. Kistorp; study nurse, D. Raae
Gentofte Hospital, Hellrup: physician, D. Haar; study nurse, U. Rasmussen
Bispbjerg Hospital, Copenhagen: physician, T. Melchior, K. Lindvig; study nurse, L. Thuesen
Herning Hospital: physician, L. Olesen; study nurse, M. Mikkelsen
Horsens Hospital: physician, A. Schmitz; study nurse, K. Larsen
Frederikshavn Hospital: physician, K. Clemmensen; study nurse, D. Bach
Thisted Hospital, Nykoping: physician, I. Nissen; study nurse, H. Emsvang
Fakse Hospital: physician, N. Rindbom Krogsgaard
Randers Hospital: physician, H. Kaspersen Nielsen; study nurse, B. Winther
Bornholm Hospital, Ronne: physician, I. Birkedal
Esbjerg Hospital: physician, A. Rohold; study nurse, L. Paarup
Amager Hospital, Copenhagen: physician, J. Bronnum-Schou; study nurse, H. Hempel
From Norway
Aker Hospital: physicians, K. Birkeland, B. Kilhovd
Rogaland Hospital, Stavanger: physicians, K. Dickstein, S. Skeie; study nurses, O. Wiig, U.M. Edland, L. Adnanes
Alesund Hospital: physician, T. Hole; study nurse, S. Olsvik
Hamar Hospital: physician, H. Kapelrud; study nurse, C. Nyvold
From Finland
Kuopio University Hospital: physician, M. Laakso; study nurses, A. Jantunen, R. Nurmi
Turku University Hospital: physician, T. Ronnemaa
Kotka Hospital: study nurse, M. Riihela
From The Netherlands
Erasmus MC/Dijksigt Hospital, Rotterdam: physicians, A.H. Bootsma, J. Dekkers; study nurse, S. Versluis
Haven Hospital, Rotterdam: physician, C.M. Leenders; study nurse, P. Klauwen
Ikazia Hospital, Rotterdam: physician, A. van Zandberger; study nurse, C. Leunis
Sint Franciscus Hospital, Rotterdam: physician, S. Mulder; study nurse, R. Erkelens
Vlietland/Schieland Hospital: physician, N. Kramer; study nurse, M. Jonas van Dijk
Zuider Hospital, Rotterdam: study nurse, M. van der Knaap
Ijsselland Hospital: study nurse, I. Hendriks
From the UK
Royal Infirmary of Edingburgh: physician, N. Boon; study nurse, L. Flint
North Tyneside General Hospital, North Shields: physician, N. Lewis-Barned; study nurses, L. Aitchison, J. Craig
Royal Devon and Exeter Hospital, Exeter: physician, K. Macleod; study nurse, S. Havill
Derriford Hospital, Plymouth: physician, A. Millward; study nurse, S. Wilkis
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TopAbstractIntroductionMethodsResultsDiscussionConclusionsAcknowledgementsAppendix: DIGAMI 2 InvestigatorsReferences |
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[Abstract/Free Full Text] - Norhammar A, Malmberg K, Rydén L, Tornvall P, Stenestrand U, Wallentin L for the Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA). Under-utilisation of evidence-based treatment partial explanation for the unfavourable prognosis in diabetic patients with acute myocardial infarction. Eur Heart J 2003;24:838–844.
[Abstract/Free Full Text] - Granger CB, Califf RM, Young S, Candela R, Samaha J, Worley S, Kereiakes DJ, Topol EJ. Outcome of patients with diabetes mellitus and acute myocardial infarction treated with thrombolytic agents. The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) Study Group. J Am Coll Cardiol 1993;21:920–925.[Abstract]
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[Abstract/Free Full Text] - Norhammar A, Malmberg K, Diderholm E, Lagerqvist B, Lindahl B, Rydén L, Wallentin L. Diabetes mellitus: the major risk factor in unstable coronary artery disease even after consideration of the extent of coronary artery disease and benefits of revascularization. J Am Coll Cardiol 2004;43:585–591.
[Abstract/Free Full Text] - Rydén L, Malmberg K. Treatment of coronary heart disease in patients with diabetes. In: Stanley W, Rydén L, eds. The Diabetic Coronary Patient. London: Science Press Ltd; 2003.
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- Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, Wedel H, Welin L. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57–65.[Abstract]
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[Abstract/Free Full Text] - The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Acute myocardial infarction: pre-hospital and in-hospital management. Eur Heart J 1996;17:43–63.
[Free Full Text] - Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, Julian D, Lengyel M, Neumann FJ, Ruzyllo W, Thygesen C, Underwood SR, Vahanian A, Verheugt FW, Wijns W. Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2003;24:28–66.
[Free Full Text] - Jeppson J-O, Jerntorp P, Almer L-O, Persson Ruth, Ekberg G, Sundkvist G. Capillary blood on filter paper for determination of HbA1c by ion exchange chromotography. Diab Care 1996;19:142–145.[Abstract]
- Myocardial infarction redefined—A consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502–1516.
[Abstract/Free Full Text] - Bartnik M, Rydén L, Ferrari R, Malmberg K, Pyörälä K, Simoons M, Standl E, Soler-Soler J, Öhrvik J, on behalf of the Euro Heart Survey Investigators. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe. The Euro Heart Survey on diabetes and the heart. Eur Heart J 2004;25:1880–1890.
[Abstract/Free Full Text] - Bassand JP, Martin J, Rydén L, Simoons M. The need for resources for clinical research: proceedings of a policy conference held at the European Heart House, 27–28 June 2002: executive summary. Eur Heart J 2003;24:1171–1173.
[Abstract/Free Full Text] - De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Manger-Cats V, Orth-Gomér K, Perk J, Pyörälä K, Rodicia JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D. European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2003;24:1601–1610.
[Free Full Text] - Liebl A, Mata M, Eschwege E on behalf of the CODE-2 Advisory Board. Evaluation of risk factors for development of complications in type 2 diabetes in Europe. Diabetologia 2002;45:S23–S28.[CrossRef][Web of Science][Medline]
- Brown JB, Nichols GA. Slow response to loss of glycemic control in type 2 diabetes mellitus. Am J Manag Care 2003;9:213–217.[Web of Science][Medline]
- Gudbjörnsdottir S, Cederholm J, Nilsson PM, Eliasson B. Steering Committee of the Swedish National Diabetes Register. The National Diabetes Register in Sweden: an implementation of the St Vincent declaration for quality improvements in diabetes care. Diab Care 2003;26:1270–1276.
[Abstract/Free Full Text] - Van den Berghe G, Wouters PJ, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359–1367.
[Abstract/Free Full Text] - Van den Berghe G, Wouters PJ, Bouillon R, Weekers F, Verwaest C, Schetz M, Vlasselaers D, Ferdinande F, Lauwers P. Outcome benefit of insulin therapy in the crtitical ill: insulin dose versus glycemic control. Crit Care Med 2003;31:359–366.[CrossRef][Web of Science][Medline]
- Fath-Ordoubadi F, Beatt KJ. Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomised placebo-controlled trials. Circulation 1997;96:1152–1156.
[Abstract/Free Full Text] - Diaz R, Paolasso EA, Leopoldo SP, Tajer CD, Gil Moreno M, Corvalàn R, Isea JE, Romero G on behalf of the ECLA. Collaborative Group. Metabolic modulation of acute myocardial infarction. The ECLA. Glucose-Insulin-Potassium pilot trial. Circulation 1998;98:2227–2234.
[Abstract/Free Full Text] - Gitt A, Schiele R, Wienbergen H, Zeymer U, Schneider S, Gottwik MG, Senges J. MITRA study. Intensive treatment of coronary artery disease in diabetic patients in clinical pactice: results of the MITRA study. Acta Diabetol 2003;40:S343–S347.
- Otter W, Kleybrink S, Doerig W, Standl E, Schnell O. Hospital outcome of acute myocardial infarction in patients with and without diabetes mellitus. Diab Med 2004;21:183–187.[CrossRef][Web of Science][Medline]
- Schnell O, Doering W, Schäfer O, Standl E, Kleybrink S, Otter W. Intensification of therapeutic approaches reduces mortality in diabetic patients with acute myocardial infarction. The Munich registry. Diab Care 2004;27:455–460.
[Abstract/Free Full Text]
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Related articles in EHJ:
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D. Mudespacher, D. Radovanovic, E. Camenzind, M. Essig, O. Bertel, P. Erne, F. R. Eberli, and F. Gutzwiller Admission glycaemia and outcome in patients with acute coronary syndrome Diabetes and Vascular Disease Research, December 1, 2007; 4(4): 346 - 352. [Abstract] [PDF]
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A. Kapur and R. De Palma Mortality after myocardial infarction in patients with diabetes mellitus Heart, December 1, 2007; 93(12): 1504 - 1506. [Abstract] [Full Text] [PDF]
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A. Norhammar, J. Lindback, L. Ryden, L. Wallentin, U. Stenestrand, and on behalf of the Register of Information and Knowl Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission Heart, December 1, 2007; 93(12): 1577 - 1583. [Abstract] [Full Text] [PDF]
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C Weston, L Walker, J Birkhead, and National Audit of Myocardial Infarction Project, N Early impact of insulin treatment on mortality for hyperglycaemic patients without known diabetes who present with an acute coronary syndrome Heart, December 1, 2007; 93(12): 1542 - 1546. [Abstract] [Full Text] [PDF]
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A. Grainger, K. Eiden, J. Kemper, and D. Reeds A Pilot Study to Evaluate the Effectiveness of Glargine and Multiple Injections of Lispro in Patients With Type 2 Diabetes Receiving Tube Feedings in a Cardiovascular Intensive Care Unit Nutr Clin Pract, October 1, 2007; 22(5): 545 - 552. [Abstract] [Full Text] [PDF]
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M. Wallander, A. Norhammar, K. Malmberg, J. Ohrvik, L. Ryden, and K. Brismar IGF Binding Protein 1 Predicts Cardiovascular Morbidity and Mortality in Patients With Acute Myocardial Infarction and Type 2 Diabetes Diabetes Care, September 1, 2007; 30(9): 2343 - 2348. [Abstract] [Full Text] [PDF]
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J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): e1 - e157. [Full Text] [PDF]
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J. L. Anderson, C. D. Adams, E. M. Antman, C. R. Bridges, R. M. Califf, D. E. Casey Jr, W. E. Chavey II, F. M. Fesmire, J. S. Hochman, T. N. Levin, et al. ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation Myocardial Infarction) Developed in Collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine J. Am. Coll. Cardiol., August 14, 2007; 50(7): 652 - 726. [Full Text] [PDF]
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Authors/Task Force Members, J.-P. Bassand, C. W. Hamm, D. Ardissino, E. Boersma, A. Budaj, F. Fernandez-Aviles, K. A.A. Fox, D. Hasdai, E. M. Ohman, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: The Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology Eur. Heart J., July 1, 2007; 28(13): 1598 - 1660. [Full Text] [PDF]
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A. D. Hafstad, A. M. Khalid, O.-J. How, T. S. Larsen, and E. Aasum Glucose and insulin improve cardiac efficiency and postischemic functional recovery in perfused hearts from type 2 diabetic (db/db) mice Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1288 - E1294. [Abstract] [Full Text] [PDF]
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C. Berry, J.-C. Tardif, and M. G. Bourassa Coronary Heart Disease in Patients With Diabetes: Part I: Recent Advances in Prevention and Noninvasive Management J. Am. Coll. Cardiol., February 13, 2007; 49(6): 631 - 642. [Abstract] [Full Text] [PDF]
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M. I. Worthley, A. S. Holmes, S. R. Willoughby, A. M. Kucia, T. Heresztyn, S. Stewart, Y. Y. Chirkov, C. J. Zeitz, and J. D. Horowitz The Deleterious Effects of Hyperglycemia on Platelet Function in Diabetic Patients With Acute Coronary Syndromes: Mediation by Superoxide Production, Resolution With Intensive Insulin Administration J. Am. Coll. Cardiol., January 23, 2007; 49(3): 304 - 310. [Abstract] [Full Text] [PDF]
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Authors/Task Force Members, L. Ryden, E. Standl, M. Bartnik, G. Van den Berghe, J. Betteridge, M.-J. de Boer, F. Cosentino, B. Jonsson, M. Laakso, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases: executive summary: The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD) Eur. Heart J., January 1, 2007; 28(1): 88 - 136. [Full Text] [PDF]
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American Diabetes Association Standards of Medical Care in Diabetes--2007 Diabetes Care, January 1, 2007; 30(suppl_1): S4 - S41. [Full Text] [PDF]
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M. Lenzen, L. Ryden, J. Ohrvik, M. Bartnik, K. Malmberg, W. Scholte op Reimer, M. L. Simoons, and on behalf of the Euro Heart Survey Investigators Diabetes known or newly detected, but not impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro Heart Survey on diabetes and the heart Eur. Heart J., December 2, 2006; 27(24): 2969 - 2974. [Abstract] [Full Text] [PDF]
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S. E. Inzucchi Management of Hyperglycemia in the Hospital Setting N. Engl. J. Med., November 2, 2006; 355(18): 1903 - 1911. [Full Text] [PDF]
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J D Newton and I B Squire Glucose and haemoglobin in the assessment of prognosis after first hospitalisation for heart failure Heart, October 1, 2006; 92(10): 1441 - 1446. [Abstract] [Full Text] [PDF]
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H. Soran, B. Barzangy, and N. Younis The benefits of insulin therapy following acute myocardial infarction revisited QJM, September 1, 2006; 99(9): 635 - 637. [Full Text] [PDF]
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The ACE/ADA Task Force on Inpatient Diabetes American College of Endocrinology and American Diabetes Association Consensus Statement on Inpatient Diabetes and Glycemic Control: A call to action Diabetes Care, August 1, 2006; 29(8): 1955 - 1962. [Full Text] [PDF]
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P. Valensi and G. Slama Review: Sulphonylureas and cardiovascular risk: facts and controversies The British Journal of Diabetes & Vascular Disease, July 1, 2006; 6(4): 159 - 165. [Abstract] [PDF]
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A. Goyal, K. W. Mahaffey, J. Garg, J. C. Nicolau, J. S. Hochman, W. D. Weaver, P. Theroux, G. B.F. Oliveira, T. G. Todaro, C. F. Mojcik, et al. Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study Eur. Heart J., June 1, 2006; 27(11): 1289 - 1297. [Abstract] [Full Text] [PDF]
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M. Vogelzang and F. Zijlstra Glucose metabolism and acute myocardial infarction Eur. Heart J., June 1, 2006; 27(11): 1264 - 1265. [Full Text] [PDF]
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M. Yngen, A. Norhammar, P. Hjemdahl, and N H. Wallen Effects of improved metabolic control on platelet reactivity in patients with type 2 diabetes mellitus following coronary angioplasty Diabetes and Vascular Disease Research, May 1, 2006; 3(1): 52 - 56. [Abstract] [PDF]
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R. W Mccallum and M. Fisher Review: Comparing cardiovascular outcomes in diabetes studies The British Journal of Diabetes & Vascular Disease, May 1, 2006; 6(3): 111 - 118. [Abstract] [PDF]
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C. Nielson, T. Lange, and N. Hadjokas Blood Glucose and Coronary Artery Disease in Nondiabetic Patients Diabetes Care, May 1, 2006; 29(5): 998 - 1001. [Abstract] [Full Text] [PDF]
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J. R. Timmer, T. Svilaas, J. P. Ottervanger, J. P.S. Henriques, J.-H. E. Dambrink, S. A.J. van den Broek, I. C.C. van der Horst, and F. Zijlstra Glucose-Insulin-Potassium Infusion in Patients With Acute Myocardial Infarction Without Signs of Heart Failure: The Glucose-Insulin-Potassium Study (GIPS)-II J. Am. Coll. Cardiol., April 18, 2006; 47(8): 1730 - 1731. [Full Text] [PDF]
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N. W. Cheung, V. W. Wong, and M. McLean The Hyperglycemia: Intensive Insulin Infusion In Infarction (HI-5) Study: A randomized controlled trial of insulin infusion therapy for myocardial infarction Diabetes Care, April 1, 2006; 29(4): 765 - 770. [Abstract] [Full Text] [PDF]
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J.R. Timmer, J.P. Ottervanger, H.J.G. Bilo, J.H.E. Dambrink, K. Miedema, J.C.A. Hoorntje, and F. Zijlstra Prognostic value of admission glucose and glycosylated haemoglobin levels in acute coronary syndromes QJM, April 1, 2006; 99(4): 237 - 243. [Abstract] [Full Text] [PDF]
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A. G. Pittas, R. D. Siegel, and J. Lau Insulin Therapy and In-Hospital Mortality in Critically Ill Patients: Systematic Review and Meta-analysis of Randomized Controlled Trials JPEN J Parenter Enteral Nutr, March 1, 2006; 30(2): 164 - 172. [Abstract] [Full Text] [PDF]
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