This is precisely what Mellbin and associates have done. Finally, use of secondary end points in post hoc analyses, especially when they were negative in the original report, is especially prone to overinterpretation. All of the differences in the current report are related to the secondary end points, even though the authors of the original DIGAMI 2 study did not report any differences in these secondary end points. Why does this approach raise such a serious concern? Finally, statistical adjustment for multiple variables is markedly limited with a small number of events. Our findings have important implications for the analysis and interpretation of clinical studies.
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Search Menu Aims Patients with diabetes have an unfavourable prognosis after an acute myocardial infarction. 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.
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. At randomization, HbA1c was 7. Blood glucose was significantly reduced after 24 h in all groups, more in groups 1 and 2 9. The corresponding values for fasting blood glucose were 8.
The study mortality groups 1—3 combined was Mortality between groups 1 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.
See page for the editorial comment on this article doi 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.
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. 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.
After an average of 3. 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.
Methods 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.
Patient recruitment started in January and ended in May Follow-up for mortality and morbidity was concluded in December 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. 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.
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. The presence or absence of previous insulin treatment was also taken into account.
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. 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. 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. 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. 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. 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. These assumptions would require a sample size of patients in groups 1 and 2 and patients in group 3 for a two-tailed test with an alpha-value of 0. 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.
SAS version was used for all statistical analyses. The Steering Committee decided to stop patient recruitment on 21 May , with the final follow-up scheduled for 15 December The reason was slow patient recruitment.
No patient was lost to follow-up. Almost all remaining patients had coronary artery disease mostly presenting as unstable angina pectoris. 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. 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.
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. 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 average increase in body weight was 4. Mortality-intention to treat Overall, there were deaths in the study After 2 years of follow-up, the Kaplan—Meier estimated mortality was The corresponding proportion in group 3 was The adjusted HR for the slight imbalance in previous diseases between groups 1 and 3 was 1. Gender did not influence mortality. 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.
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.
Morbidity There was a trend towards fewer secondary events in groups 2 and 3 compared with group 1. Discussion 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 patients, was stopped prematurely owing to the slow patient recruitment rate.
When viewed with other browsers, some characters or attributes may not be rendered correctly. From Research to Practice and Coronary Heart Disease In Brief People with diabetes who suffer an acute myocardial infarction MI are at markedly increased risk of future cardiovascular morbidity and mortality. The DIGAMI study compared "conventional" anti-diabetic therapy to intensive insulin therapy consisting of acute insulin infusion during the early hours of MI and thrice-daily subcutaneous insulin injection for the remainder of the hospital stay and a minimum of 3 months thereafter. Although there was an overall reduction in adverse outcomes in patients receiving the intensive insulin regimen, it is unclear which component the IV insulin infusion or the intensive chronic therapy was responsible. Josephson, MS, MD Despite many advances in modern medicine, diabetes mellitus continues to be associated with increased morbidity and mortality.
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