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21st July 2009
This large trial found no benefit in rates of survival or major vascular events from early versus later revascularisation in people with type 2 diabetes and coronary artery disease. There was also no difference seen in those given ‘insulin sensitisation’ (using drugs such as metformin) compared with ‘insulin provision’ (using insulin/sulphonylureas). Participants were primarily non-smokers and all received intensive medical therapy to control blood pressure, blood lipids and blood glucose. Severe hypoglycaemia was more common in the insulin provision group than the insulin sensitisation group.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Action
Health professionals should continue to follow NICE guidance on the care of people with type 2 diabetes. Even in people with established heart disease, attending to modifiable risk factors such as smoking, blood pressure control and blood lipids can reduce their cardiovascular risk substantially. Early revascularisation (except perhaps in those at highest baseline risk) does not seem to confer advantages over intensive medical therapy. Relying on insulin and sulphonylureas (instead of using drugs such as metformin) to control blood glucose increases the risk of severe hypoglycaemia.
What is the background to this?
People with type 2 diabetes, especially those with established coronary artery disease, have a greater risk of cardiovascular (CV) events and death from CV causes than those without diabetes. This study investigated whether early revascularisation to manage coronary artery stenosis in such people increases survival and reduces the risk of CV events, compared to forgoing such interventions unless and until revascularisation becomes clinically indicated (e.g. development of acute coronary syndrome [ACS] or progression of angina). This study looked at the effects of revascularisation by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI). Revascularisation was performed in within 6 months in 95.4% of patients in the early revascularisation group, compared with 13.0% of the comparison group. However, at 5 years, 42.1% of people in the comparison group had undergone clinically indicated revascularisation.
There are also theoretical reasons and some trial evidence to support a strategy of using ‘insulin sensitising’ drugs such as metformin over a strategy of ‘insulin provision’ (such as using sulphonylureas and insulin) to control blood glucose, and this study investigated that as well. The target HbA1c was less than 7.0% (53mmol/mol)
All patients were candidates for CABG or PCI. Their doctors decided which revascularisation technique would be most appropriate on clinical grounds, before patients were randomised. Thus patients were stratified by the proposed revascularisation method, before being randomised to either early or delayed revascularisation, and insulin sensitisation or insulin provision treatment.
What does this study claim?
The 5-year survival rate was not significantly different whether revascularisation occurred early or late (88.3% versus 87.8%, difference 0.5%, 95% confidence interval [CI] –2.0 to 3.1, P=0.97), nor was there any significant difference in the rate of major CV events (death, myocardial infarction or stroke): 22.8% vs 24.1%, difference 1.3%, 95%CI –2.2 to 4.9, P=0.70). There were also no significant differences in these endpoints between the two hypoglycaemic treatment strategy groups.
Patients for whom CABG was the prespecified method of revascularisation had more extensive coronary artery disease. Among these people, having prompt or delayed revascularisation did not affect the 5-year survival rate, but those assigned to the prompt revascularisation group had significantly fewer major CV events than those in whom revascularisation was delayed until it became clinically necessary (22.4% vs 30.5%, P=0.01, NNT=12).
Adverse events were similar between the groups, but severe hypoglycaemia was more common in the insulin provision group than the insulin sensitisation group (9.2% vs 5.9%, P=0.003, NNH=30)
So what?
This study seems to show that in people whose other modifiable risk factors have been addressed, there is nothing to be gained from early, “prophylactic” revascularisation instead of forgoing this unless and until revascularisation becomes clinically necessary (with the possible exception of those at very high baseline risk).
It is important to note that all the patients were receiving many other evidence-based interventions to reduce CV risk. Firstly, their blood pressure was well controlled (mean 132/75 mmHg at baseline, reducing to 125/70 mmHg at 3 years). At baseline, 75% of people were taking statins (and mean LDL-cholesterol was 2.5mmol/L), and at 3 years 95% were taking statins (and mean LDL-cholesterol was about 2mmol/L). Only 22% of people were smokers at baseline, and this halved to about 11% at 3 years. Aspirin and/or clopidogrel use was almost universal and 77% were taking an ACE-inhibitor or ARB at baseline, increasing to about 92% at 3 years.
Does this study show that controlling HbA1c is as good as revascularisation? After all, the Hba1c in the prompt and delayed revascularisation groups was around 7.2% (55mmol/mol). This evidence needs to be considered in the light of other evidence. A recent blog points out the conflicting nature of evidence from RCTs with regard to the benefits and risks of intensive glucose control. RCTs such as ACCORD, ADVANCE and VADT have not identified consistently a significant benefit of intensive glycaemic control in the treatment of type 2 diabetes (see blogs 258, 147 and 64 for more details) with regard to CV outcomes and mortality. Indeed, the ACCORD study was stopped early because of an increased risk of death in the intensive treatment arm.
A recent meta-analysis suggested that intensive glycaemic control therapy may have a small beneficial effect in reducing the risk of coronary heart disease, although it would appear to have no significant effect on reducing strokes or all cause mortality. This meta-analysis had some significant limitations, as we discussed in our blog, but even if these are left aside, the meta-analysis suggested that the benefits of glycaemic control on coronary outcomes are modest in comparison with the benefits that might be obtained by blood pressure control and lipid modification. We have consistently pointed out in other blogs and NPC materials on type 2 diabetes the need to consider glycaemic control in the context of other important interventions (both lifestyle and drug interventions) to reduce CV risk. In the study discussed here, these interventions had largely all been made, so any absolute beneficial effect of glycaemic control would probably have been very small.
The study found no difference between an insulin provision strategy and an insulin sensitisation strategy in reducing mortality or major CV events. However, attempting tight glycaemic control with insulins and sulphonylureas led to more, severe hypoglycaemic episodes than a strategy of using metformin and glitazones. The insulin sensitisation drugs used in this study were metformin and glitazones. Taken with the evidence that glitazones may increase the risk of heart failure, double the risk of bone fracture in women, and some evidence to suggest that rosiglitazone, in particular, may be associated with an increased risk of myocardial infarction, NICE’s recommendation to use metformin as the first choice oral hypoglycaemic seems wise.
More information on type 2 diabetes can be found on the type 2 diabetes section of NPC.
Study details
Patients: 2,368 patients with type 2 diabetes and coronary artery disease, who were candidates for CABG or PCI
Intervention and comparison: Patients were stratified by intention to use PCI (n=1,605) or CABG (n=763), then randomised in a 2×2 factorial fashion to undergo prompt revascularisation (within 4 weeks) or intensive medical therapy only, unless and until revascularisation became clinically necessary; and to insulin sensitisation or insulin provision therapy to achieve HbA1c less than 7.0% (53mmol/mol).
Outcomes and results The five-year survival rate was not significantly different whether revascularisation occurred early or late (88.3% versus 87.8%, difference 0.5%, 95%CI –2.0 to 3.1, P=0.97), nor was there a significant difference in the rate of major CV events (death, myocardial infraction or stroke): 22.8% vs 24.1% respectively, difference 1.3%, 95%CI –2.2 to 4.9, P=0.70). There were also no significant differences in these endpoints between the two hypoglycaemic treatment strategy groups: five- year survival rate 88.2% in insulin sensitisation group vs 87.9% in the insulin provision group, difference 0.3%, 95%CI –2.2 to 2.9, P=0.89; major CV events 22.3% vs 24.6%, difference 2.4%, 95%CI –1.2 to 6.0, P=0.13).
Adverse events were similar between the groups, but severe hypoglycaemia was more common in the insulin provision group than the insulin sensitisation group (9.2% vs 5.9%, P=0.003, NNH=30)
Sponsorship: Supported by grants from the National Heart, Lung and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases; and by GlaxoSmithKline, Lantheus Medical Imaging, Astellas Pharma, Merck, Abbott Laboratories, Pfizer, MediSense, Bayer, Becton Dickinson, J.R. Carlson Labs, Centocor, Eli Lilly, LipoScience, Novartis, and Novo Nordisk.
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