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The Trial of Intravenous Insulin Infusion in the Management of Hyperglycaemia in Acute Coronary Syndrome

Joint venture ABCD, NHS Diabetes, British Cardiovascular Society, Myocardial Ischaemia National Audit project (MINAP)

Approximately 85% patients presenting with acute coronary syndromes (ACS) have dysglycaemia. There is increasing evidence that high blood glucose (BG) levels in patients with known diabetes and also those with new stress hyperglycaemia, is associated with worse outcomes in ACS and that strict glycaemic control may improve outcomes[1-5] There have been no randomised control trials (RCTs) comparing strict glycaemic control versus less strict; hence, there are no agreed targets for glycaemic control in the management of ACS. However, there is evidence from one RCT that treatment with insulin in the acute phase and for 3 months after the event has a mortality benefit for up to 3 years [6]. Observational data from the MINAP database showed that treatment with insulin in patients without known diabetes and ACS with a glucose ≥ 11mmol was associated with a reduced adjusted hazard ratio of death within 7 days [7]. A recent study from the US showed improved outcomes for those in whom hyperglycaemia resolved spontaneously or with insulin treatment [8].

Aims of TITAN-ACS Study
To evaluate effectiveness of a variable rate intravenous insulin (VRIII) administered with concomitant 5% dextrose and potassium (40 mmol/L) infusion for patients with ACS presenting with an admission glucose of ≥ 10 mmol/L.

To use the information derived from these data develop practical guidance for management of hyperglycaemia in ACS that would be applicable for use nationally and in agreement with other consensus guidance under the auspices of the Joint British Diabetes Societies Inpatient care Group.
The following primary outcomes are be examined:
To confirm that use of a standardised VRIII with 5% glucose and potassium

• Was effective in achieving normoglycaemia – time to reach 8mmol
• Was effective in maintaining normoglycaemia - median glucose measurements within the range 4-8 mmol in the first 24 hours
• Was not associated with increased frequency of either mild hypoglycaemia BG < 4mmol/L or severe hypoglycaemia BG < 3 mmol/L
• Was not associated with insulin-induced hypokalaemia
• Was not associated with an excess of cardiac arrythmias

The following secondary outcomes are to be examined:
• To use the MINAP audit data to examine whether there was a mortality benefit for those in the TITAN-ACS STUDY receiving a standardised VRIII titrated to achieve normoglycaemia .

Principal investigator: Dr M Sinclair Hammersley, Oxford University Hospitals
MINAP Coordinator: Dr John Birkhead, National Institute of Clinical Outcomes, The Heart Hospital, London

Time Frame
Start: January 2010
Finish: December 2011
Primary outcome data: Diabetes UK APC 2012 Posters 577 and 581
Secondary outcome data: June 2012
Guideline: For completion by March 2013

1) Hadjadj S, Coisne D, Mauco G, Ragot S, Duengler F, Sosner P, Torremocha F, Herpin D, Marechaud R. Prognostic value of admission plasma glucose and HbA1c in acute myocardial infarction. Diabetic Medicine 2004; 21 (4), 305–310
2) Stranders I, Diamant M, Van Gelder R E, Spruijt H J, Twisk JWR, Heine R J, Visser F C. Admission Blood Glucose Level as Risk Indicator of Death After Myocardial Infarction in Patients With and Without Diabetes Mellitus. Arch Intern Med 2004;164:982-988.
3) Ceriello, A. Acute hyperglycaemia: a ‘new’ risk factor during myocardial infarction. European Heart Journal 2005; 26: 328 - 331.
4) Zarich SW, Nesto RW, Implications and Treatment of Acute Hyperglycemia in the Setting of Acute Myocardial Infarction Circulation. 2007;115:e436-e439.
5) Iwakura K, Ito H, MD, Ikushima M, MD*, Kawano S, Okamura A, Asano K, Kuroda T, Tanaka K, Masuyama T, Hori M, and Fujii K. Association between hyperglycemia and the no-reflow phenomenon inpatients with acute myocardial infarction. Am Coll Cardiol, 2003; 41:1-7
6) Malberg and DIGAMI Study group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ 1997; 314: 1512-1515
7) Weston C, Walker L, Birkhead J. Early impact of insulin treatment on mortality for hyperglycaemic patients without known diabetes who present with an acute coronary syndrome. Heart 2007; 93: 1542 – 1546
8) Kosiborod M, Inzucchi SE, Krumholz HM, Masoudi FA, Goyal A, Xiao L, Jones PG, Fiske S, Spertus JA. Glucose normalization and outcomes in patients with acute myocardial infarction. Arch Intern Med. 2009 169:438-46.

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