Randomised control trial
Malmberg K, Ryden L, Wedel H, et alIntense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity
European Heart Journal
2005: 26 650-661
- Submitted by:Craig Ferguson - SPR
- Institution:Salford Royal Foundation Trust
- Date submitted:23rd July 2007
1
Objectives and hypotheses
1.1
Are the objectives of the study clearly stated?
Rather vague objective stated in the introduction, "to further explore the possible benefits of an insulin-based management of diabetic patients with myocardial infarction."
Stated more specifically in methods section, "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... among the three groups."
Group 1 was 24h insulin/glucose infusion followed by s/c insulin, Group 2 was the infusion followed by standard treatment and Group 3 was standard treatment.
Stated more specifically in methods section, "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... among the three groups."
Group 1 was 24h insulin/glucose infusion followed by s/c insulin, Group 2 was the infusion followed by standard treatment and Group 3 was standard treatment.
2
Design
2.1
Is the study design suitable for the objectives
Study design was suitable but not clear why changed inclusion criteria from those of the DIGAMI 1 trial.
2.2
Who / what was studied?
Patients with established type 2 diabetes or patients with an admission blood glucose >11mmol/l who were admitted with a suspected myocardial infarction to one of 44 international centres.
2.3
Was this the right sample to answer the objectives?
Not sure why patients with type 1 diabetes but a blood glucose <11mmol/l were not included.
2.4
Is the study large enough to achieve its objectives? Have sample size estimates been performed?
A sample size was estimated. Expected a 30% 2 year mortality in the control group, 23% mortality in group 2 and 17% mortality in group 1 patients. Figures appear to have been esimated based on the results from the DIGAMI 1 trial but not very clear how.
Estimated sample required was 1150 patients in groups 1 and 2 and 700 patients in group 3. Only managed to obtain 1253 patients before trial was stopped due to slow recruitment.
Estimated sample required was 1150 patients in groups 1 and 2 and 700 patients in group 3. Only managed to obtain 1253 patients before trial was stopped due to slow recruitment.
2.5
Were all subjects accounted for?
Yes. States no patients lost to follow up.
2.6
Were all appropriate outcomes considered?
Do consider stroke, reinfarction and death as outcomes.
2.7
Has ethical approval been obtained if appropriate?
Yes. States ethical approval obtained at local review boards.
2.8
Were the patients randomised between treatments?
yes.
2.9
How was randomisation carried out?
Not sure really. Describes process as 'balanced randomisation'. States that took into account risk factors that had been used to stratify patients in the DIGAMI 1 trial, i.e.: age <> 70y; previous MI; previous heart failure; treatment with digitalis; presence of insulin. Randomisation was based on algorithm incorporating these factors.
Despite deliberately manipulating the randomisation process there were, "significantly fewer previous myocardial infarctions and a trend towards less hypertension and heart failure in group 3."
In the discussion the authors state that the slow recruitment rate and the fact that some centres recruited relatively few patients explained the imbalance between groups as the randomisation algorithm was not applied until eight patients were included in an individual centre. They state that,"this caused the patients in group 3 to be somewhat less sick than those in groups 2 and 3." Presumably they meant patients in group 3 were not as sick as patients in groups 1 and 2 but I still don't understand how.
Despite deliberately manipulating the randomisation process there were, "significantly fewer previous myocardial infarctions and a trend towards less hypertension and heart failure in group 3."
In the discussion the authors state that the slow recruitment rate and the fact that some centres recruited relatively few patients explained the imbalance between groups as the randomisation algorithm was not applied until eight patients were included in an individual centre. They state that,"this caused the patients in group 3 to be somewhat less sick than those in groups 2 and 3." Presumably they meant patients in group 3 were not as sick as patients in groups 1 and 2 but I still don't understand how.
2.10
Are the outcomes clinically relevant?
Yes. Reinfarction, stroke and death are all clinically relevant.
3
Measurement and observation
3.1
Is it clear what was measured, how it was measured and what the outcomes were?
What was measured was clear. Outcomes were provided in the form of Kaplan-Meier graphs. Figures were provided for the Kaplan-Meier estimated mortality at 2 years with hazard ratios given for the difference between groups.
In the DIGAMI 1 paper mortality rates were provided for 3 months and 1 year but this data was not provided in this paper.
In the DIGAMI 1 paper mortality rates were provided for 3 months and 1 year but this data was not provided in this paper.
3.2
Are the measurements valid?
Should be valid.
3.3
Are the measurements reliable?
Should be reliable.
3.4
Are the measurements reproducible?
Should be.
3.5
Were the patients and the investigators blinded?
No, neither. Would have been very difficult.
4
Presentation of results
4.1
Are the basic data adequately described?
Reasonable. Would have been nice if the authors had explained the randomisation algorithm that they used.
4.2
Were groups comparable at baseline?
Table 1 is provided and gives reasonable data on each of three groups.
4.3
Are the results presented clearly, objectively and in sufficient detail to enable readers to make their own judgement?
Would have been nice to provide tables with figures for the outcomes at say 3, 6, 12 and 24 months rather than just providing very small Kaplan-Meier graphs.
4.4
Are the results internally consistent, i.e. do the numbers add up properly?
I think so.
4.5
Were side effects reported?
Hypoglycaemia was the only side effect reported.
5
Analysis
5.1
Are the data suitable for analysis?
yes.
5.2
Are the methods appropriate to the data?
Yes.
5.3
Are any statistics correctly performed and interpreted?
Yes, think so.
6
Discussion
6.1
Are the results discussed in relation to existing knowledge on the subject and study objectives?
Yes. Only discusses findings relative to DIGAMI 1 trial and one other trial looking at insulin therapy in acutely ill patients in a critical care setting.
6.2
Is the discussion biased?
The discussion does lean towards explaining why they might have failed to prove a benefit that exists and does not really acknowledge the possibility that there may not be a benefit.
7
Interpretation
7.1
Are the authors' conclusions justified by the data?
Authors conclude:
1. trial did not show survival benefit in type 2 diabetics with MI treated with insulin
2. insulin treatment in these patients does not reduce risk of further MI or stroke
3. Glucose level on admission is a predictor of long-term mortality
4. Glucose control is an important part of their management
I agree with the first 3 findings. I do not think the paper demonstrated that glucose control affected outcome.
1. trial did not show survival benefit in type 2 diabetics with MI treated with insulin
2. insulin treatment in these patients does not reduce risk of further MI or stroke
3. Glucose level on admission is a predictor of long-term mortality
4. Glucose control is an important part of their management
I agree with the first 3 findings. I do not think the paper demonstrated that glucose control affected outcome.
7.2
What level of evidence has this paper presented? (using CEBM levels)
1b
7.3
Does this paper help me answer my problem?
Starting intensive insulin therapy to manage hyperglycaemia in patients with MIs has a good theory behind it and the DIGAMI 1 trial appeared to show a definite if not quite statistically significant benefit. The patients in this trial who had a intensive treatment actually fared worse than the patients on standard treatment though again the results were not significant.
There does not appear to be any clear cut benefit or harm from treating these patients with an intensive insulin regimen.
There does not appear to be any clear cut benefit or harm from treating these patients with an intensive insulin regimen.
8
Implementation
8.1
Can any necessary change be implemented in practice?
?
8.2
What aids to implementation exist?
8.3
What barriers to implementation exist?