Management of Acute Coronary Syndromes

Abstract

Key Messages•Diabetes is an independent predictor of increased short- and long-term mortality, recurrent myocardial infarction (MI) and the development of heart failure in patients with acute MI (AMI).•Patients with an AMI and hyperglycemia should receive insulin-glucose infusion therapy to maintain blood glucose between 7.0 and 10.0 mmol/L for at least 24 hours, followed by strategies to achieve recommended glucose targets long term.•People with diabetes are less likely to receive recommended treatment, such as revascularization, thrombolysis, beta blockers or acetylsalicylic acid than people without diabetes. Efforts should be directed at promoting adherence to existing proven therapies in the high-risk patient with MI and diabetes. •Diabetes is an independent predictor of increased short- and long-term mortality, recurrent myocardial infarction (MI) and the development of heart failure in patients with acute MI (AMI).•Patients with an AMI and hyperglycemia should receive insulin-glucose infusion therapy to maintain blood glucose between 7.0 and 10.0 mmol/L for at least 24 hours, followed by strategies to achieve recommended glucose targets long term.•People with diabetes are less likely to receive recommended treatment, such as revascularization, thrombolysis, beta blockers or acetylsalicylic acid than people without diabetes. Efforts should be directed at promoting adherence to existing proven therapies in the high-risk patient with MI and diabetes. Diabetes (together with lipid abnormalities, smoking and hypertension) is 1 of the top 4 independent risk factors for myocardial infarction (MI) (1Yusuf S. Hawken S. Ounpuu S. et al.Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.Lancet. 2004; 364: 937-952Abstract Full Text Full Text PDF PubMed Scopus (8433) Google Scholar). Today, approximately 15% to 35% of patients admitted with an acute coronary syndrome (ACS) have known diabetes (2Ovbiagele B. Markovic D. Fonarow G.C. Recent US patterns and predictors of prevalent diabetes among acute myocardial infarction patients.Cardiol Res Pract. 2011; : 145615PubMed Google Scholar), and as many as another 15% have undiagnosed diabetes (3Aguilar D. Solomon S.D. Kober L. et al.Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.Circulation. 2004; 110: 1572-1578Crossref PubMed Scopus (207) Google Scholar). Compared to individuals without diabetes, patients with diabetes have:1.A 3-fold increased risk of ACS (4Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar),2.Occurrence of acute coronary events 15 years earlier (4Booth G.L. Kapral M.K. Fung K. Tu J.V. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study.Lancet. 2006; 368: 29-36Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar).3.A 2-fold increased short- (5Donahoe S.M. Stewart G.C. McCabe C.H. et al.Diabetes and mortality following acute coronary syndromes.JAMA. 2007; 298: 765-775Crossref PubMed Scopus (543) Google Scholar, 6Behar S. Boyko V. Reicher-Reiss H. Goldbourt U. Ten-year survival after acute myocardial infarction: comparison of patients with and without diabetes. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial.Am Heart J. 1997; 133: 290-296Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar) and long-term mortality (5Donahoe S.M. Stewart G.C. McCabe C.H. et al.Diabetes and mortality following acute coronary syndromes.JAMA. 2007; 298: 765-775Crossref PubMed Scopus (543) Google Scholar, 7Kumler T. Gislason G.H. Kober L. Torp-Pedersen C. Diabetes is an independent predictor of survival 17 years after myocardial infarction: follow-up of the TRACE registry.Cardiovasc Diabetol. 2010; 9: 22Crossref PubMed Scopus (15) Google Scholar, 8Malmberg K. Yusuf S. Gerstein H.C. et al.Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry.Circulation. 2000; 102: 1014-1019Crossref PubMed Scopus (657) Google Scholar).4.An increased incidence of post-infarction recurrent ischemic events, heart failure and cardiogenic shock (3Aguilar D. Solomon S.D. Kober L. et al.Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.Circulation. 2004; 110: 1572-1578Crossref PubMed Scopus (207) Google Scholar, 9Kannel W.B. Thomas Jr., H.E. Sudden coronary death: the Framingham Study.Ann N Y Acad Sci. 1982; 382: 3-21Crossref PubMed Scopus (196) Google Scholar).5.A similar benefit from guideline recommended management strategies (see below.)6.Less utilization of guideline recommended care (10Hasin T. Hochadel M. Gitt A.K. et al.Comparison of treatment and outcome of acute coronary syndrome in patients with versus patients without diabetes mellitus.Am J Cardiol. 2009; 103: 772-778Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 11Hung J. Brieger D.B. Amerena J.V. et al.Treatment disparities and effect on late mortality in patients with diabetes presenting with acute myocardial infarction: observations from the ACACIA registry.Med J Aust. 2009; 191: 539-543PubMed Google Scholar, 12Norhammar A. Lindback J. Ryden L. et al.Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA)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. 2007; 93: 1577-1583Crossref PubMed Scopus (131) Google Scholar, 13Brogan Jr., G.X. Peterson E.D. Mulgund J. et al.Treatment disparities in the care of patients with and without diabetes presenting with non-ST-segment elevation acute coronary syndromes.Diabetes Care. 2006; 29: 9-14Crossref PubMed Scopus (60) Google Scholar), which may contribute to adverse outcomes in the patient with diabetes (14Yan R.T. Yan A.T. Tan M. et al.Underuse of evidence -based treatment partly explains the worse clinical outcomes in diabetic patients with acute coronary syndromes.Am Heart J. 2006; 152: 676-683Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). Although the absolute number of patients with MI has fallen in the United States, the prevalence of diabetes in this population has steadily increased from 18% in 1997 to 30% in 2006 (2Ovbiagele B. Markovic D. Fonarow G.C. Recent US patterns and predictors of prevalent diabetes among acute myocardial infarction patients.Cardiol Res Pract. 2011; : 145615PubMed Google Scholar). More than two-thirds of patients with MI have either diabetes or impaired glucose regulation (impaired glucose tolerance and impaired fasting glucose) (15Bartnik M. Ryden L. Ferrari R. et al.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: 1880-1890Crossref PubMed Scopus (577) Google Scholar). Abnormal glucose regulation is almost twice as prevalent in patients with MI compared to a matched control population and is a marker for adverse outcomes (16Bartnik M. Malmberg K. Hamsten A. et al.Abnormal glucose tolerance: a common risk factor in patients with acute myocardial infarction in comparison with population-based controls.J Intern Med. 2004; 256: 288-297Crossref PubMed Scopus (77) Google Scholar). The frequency of previously unrecognized diabetes in the ACS population is reported to be between 4% and 22% depending on the test used for the diagnosis of diabetes (3Aguilar D. Solomon S.D. Kober L. et al.Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial.Circulation. 2004; 110: 1572-1578Crossref PubMed Scopus (207) Google Scholar, 17Mozaffarian D. Marfisi R. Levantesi G. et al.Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors.Lancet. 2007; 370: 667-675Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). If fasting glucose criteria is used alone in the ACS population, diabetes is underdiagnosed in 39% compared to when the diagnosis is made from an oral glucose tolerance test (OGTT) (18Bartnik M. Ryden L. Malmberg K. et al.Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart.Heart. 2007; 93: 72-77Crossref PubMed Scopus (120) Google Scholar). Glycated hemoglobin (A1C) at or above 6.5% is currently a diagnostic criterion for diabetes as it captures long-term glucose exposure, does not require fasting or timed samples and is currently used to guide management decisions. A1C has been validated in an acute care population (19Silverman R.A. Thakker U. Ellman T. et al.Hemoglobin A1c as a screen for previously undiagnosed prediabetes and diabetes in an acute-care setting.Diabetes Care. 2011; 34: 1908-1912Crossref PubMed Scopus (43) Google Scholar). Using the OGTT as a gold standard for the diagnosis of diabetes and an A1C threshold of 6.0%, A1C had a sensitivity of 77% and a specificity of 87%. It is accepted that some patients with diabetes will be missed by screening with fasting blood glucose and A1C compared to the universal use of an OGTT. However, it is likely that the patients most in need of glycemic control will be detected with these simple tests, which can be widely applied. It has been suggested that individuals with A1C of 6.0% to 6.4% should have an OGTT 6 to 8 weeks after discharge (20Gholap N. Davies M.J. Mostafa S.A. et al.A simple strategy for screening for glucose intolerance using glycated haemoglobin, in individuals with acute coronary syndrome.Diabet Med. 2012; 29: 838-843Crossref PubMed Scopus (14) Google Scholar). Guidelines for the management of patients with ACS have been developed by the American College of Cardiology (ACC)/American Heart Association (AHA) (21Anderson J.L. Adams C.D. Antman E.M. 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, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.J Am Coll Cardiol. 2007; 50: 652-726Abstract Full Text Full Text PDF Scopus (240) Google Scholar, 22Kushner F.G. Hand M. 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Ardissino D. et al.Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes.Eur Heart J. 2007; 28: 1598-1660Crossref PubMed Scopus (48) Google Scholar). In most situations, there are no clinical trials that specifically address management of the patient with diabetes and ACS. However, subgroup analyses in patients with diabetes and ACS show either a similar or an enhanced benefit from treatment compared to the overall group for a) reperfusion with fibrinolysis (26Fibrinolytic Therapy Trialists' (FTT) Collaborative GroupIndications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients.Lancet. 1994; 343: 311-322Abstract PubMed Scopus (2818) Google Scholar) or primary angioplasty (27Timmer J.R. Van Der Horst I.C.C. et al.Comparison of myocardial perfusion after successful primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction with versus without diabetes mellitus.Am J Cardiol. 2005; 95: 1375-1377Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar) for ST-segment elevation ACS; and b) an early invasive strategy (28O'Donoghue M.L. Vaidya A. Afsal R. et al.An invasive or conservative strategy in patients with diabetes mellitus and non-ST-segment elevation acute coronary syndromes: a collaborative meta-analysis of randomized trials.J Am Coll Cardiol. 2012; 60: 106-111Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar), the use of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel (29Yusuf S. Zhao F. Mehta S.R. et al.Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med. 2001; 345: 494-502Crossref PubMed Scopus (6052) Google Scholar), and glycoprotein (GP) IIb/IIIa inhibitors in patients with non–ST-segment elevation ACS (NSTE ACS) at high risk of recurrent ischemic events (30Roffi M. Chew D.P. Mukherjee D. et al.Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes.Circulation. 2001; 104: 2767-2771Crossref PubMed Scopus (396) Google Scholar). A significant care gap exists for patients with diabetes not receiving guideline-recommended treatment compared to patients without diabetes (12Norhammar A. Lindback J. Ryden L. et al.Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA)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. 2007; 93: 1577-1583Crossref PubMed Scopus (131) Google Scholar, 13Brogan Jr., G.X. Peterson E.D. Mulgund J. et al.Treatment disparities in the care of patients with and without diabetes presenting with non-ST-segment elevation acute coronary syndromes.Diabetes Care. 2006; 29: 9-14Crossref PubMed Scopus (60) Google Scholar, 14Yan R.T. Yan A.T. Tan M. et al.Underuse of evidence -based treatment partly explains the worse clinical outcomes in diabetic patients with acute coronary syndromes.Am Heart J. 2006; 152: 676-683Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 31Hung J. Brieger D.B. Amerena J.V. et al.Treatment disparities and effect on late mortality in patients with diabetes presenting with acute myocardial infarction: observations from the ACACIA registry.Med J Aust. 2009; 191: 539-543PubMed Google Scholar). It is possible that underutilization of recommended treatment is 1 factor contributing to the adverse outcome of the ACS patient with diabetes. Platelet aggregation plays a central role in the development of the occlusive thrombus responsible for acute coronary occlusion in patients with ACS. Patients with diabetes have a prothrombotic state due to dysfunctional and hyperactive platelets, endothelial dysfunction, elevated coagulation factors and decreased fibrinolysis (32Ferreiro J.L. Angiolillo D.J. Diabetes and antiplatelet therapy in acute coronary syndrome.Circulation. 2011; 123: 798-813Crossref PubMed Scopus (253) Google Scholar). Increased platelet activity is due to multiple metabolic and cellular factors associated with diabetes that include endothelial dysfunction, the impact of hyperglycemia and deficient insulin action (32Ferreiro J.L. Angiolillo D.J. Diabetes and antiplatelet therapy in acute coronary syndrome.Circulation. 2011; 123: 798-813Crossref PubMed Scopus (253) Google Scholar). Diabetes is associated with an increased incidence of recurrent atherothrombotic events (8Malmberg K. Yusuf S. Gerstein H.C. et al.Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry.Circulation. 2000; 102: 1014-1019Crossref PubMed Scopus (657) Google Scholar), including stent thrombosis (33Iakovou I. Schmidt T. Bonizzoni E. et al.Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.JAMA. 2005; 293: 2126-2130Crossref PubMed Scopus (2935) Google Scholar). Antiplatelet therapy has been shown to reduce atherothrombotic events in patients with ACS, both during the acute phase and in the longer term. The beneficial effect of ASA has been shown in multiple clinical trials in patients with NSTE ACS and ST-elevation MI (STEMI). The Antithrombotic Trialists’ Collaboration meta-analysis of antiplatelet therapy (mainly ASA) included 212 000 high-risk patients (with acute or previous vascular disease) and showed the incidence of vascular events to be reduced in both the overall population (16.8% to 12.8%; p<0.00001) and in patients with diabetes (22.3% to 18.5%; p<0.002) (34Antithrombotic Trialists CollaborationCollaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.BMJ. 2002; 324: 71-86Crossref PubMed Google Scholar). Low-dose ASA (75 to 150 mg) was as effective as higher doses (>150 mg) with a lower incidence of bleeding complications. The CURRENT/OASIS 7 trial also was unable to show any benefit from higher-dose compared to low-dose (75 to 100 mg) ASA in patients with and without diabetes (35Mehta S.R. Tanguay J.F. Eikelboom J.W. et al.Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing percutaneous coronary intervention for acute coronary syndromes (CURRENT-OASIS 7): a randomised factorial trial.Lancet. 2010; 376: 1233-1243Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar). The use of low-dose ASA is recommended to minimize gastrointestinal bleeding in patients with and without diabetes. Dual antiplatelet therapy with ASA and clopidogrel, administered from the time of presentation, has been the recommended standard of care for patients with NSTE ACS. Patients with diabetes in the CURE trial had a similar benefit with clopidogrel vs. placebo (14.2% vs. 17.7%, relative risk [RR] 0.84, 95% confidence interval [CI] 0.70–1.02) as the overall population (9.3% vs. 11.4%, RR 0.80, 95% CI 0.72–0.90) (29Yusuf S. Zhao F. Mehta S.R. et al.Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.N Engl J Med. 2001; 345: 494-502Crossref PubMed Scopus (6052) Google Scholar). Despite dual antiplatelet therapy with ASA and clopidogrel, recurrent atherothrombotic events continue to occur, especially in patient with diabetes. Clopidogrel is a relatively weak inhibitor of platelet aggregation with a wide variation of inhibition of in vitro platelet aggregation. There is a higher incidence of events in patients with residual platelet activity, and patients with diabetes have higher residual platelet activity despite ASA and clopidogrel treatment. Two new antiplatelet agents, prasugrel and ticagrelor, which are more effective and predictable inhibitors of platelet aggregation, have recently become available in Canada. In the TRITON study, prasugrel administered at the time of coronary angioplasty in patients with ACS reduced recurrent ischemic events, including stent thrombosis, compared to patients receiving clopidogrel (36Wiviott S.D. Braunwald E. McCabe C.H. et al.TRITON-TIMI 38 Investigators Prasugrel versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2007; 357: 2001-2015Crossref PubMed Scopus (5561) Google Scholar). In subjects with diabetes, prasugrel treatment was associated with greater platelet inhibition and fewer poor responders (37Angiolillo D.J. Badimon J.J. Saucedo J.F. et al.A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial.Eur Heart J. 2011; 32: 838-846Crossref PubMed Scopus (173) Google Scholar). Prasugrel resulted in an important net clinical benefit in patients with diabetes (14.6% vs. 19.2%, hazard ratio [HR] 0.74; p=0.001) due to a 30% reduction of the primary endpoint (cardiovascular [CV] death, nonfatal MI, or stroke) over the 14.4 months of the study (38Wiviott S.D. Braunwald E. Angiolillo D.J. et al.TRITON-TIMI 38 Investigators Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-Thrombolysis in Myocardial Infarction 38.Circulation. 2008; 118: 1626-1636Crossref PubMed Scopus (685) Google Scholar). In this subgroup with diabetes, there was no significant increase in major bleeding. There was no statistical interaction between the subgroups with and without diabetes, indicating that the enhanced absolute benefit was the result of higher event rates in patients with diabetes. In the Platelet Inhibition and Patient Outcomes (PLATO) study, the P2Y12 receptor antagonist, ticagrelor, when compared with clopidogrel and administered early after presentation in patients with NSTE ACS or STEMI, reduced CV death, nonfatal MI and stroke (10.2% vs. 12.3%, HR 0.84; p=0.0001), as well as CV death (4.0% vs. 5.1%, HR 0.49; p=0.001) and stent thrombosis (2.2% vs. 2.9%, HR 0.75; p=0.02), with a modest increase in bleeding in patients not undergoing coronary bypass surgery (39Cannon C.P. Harrington R.A. James S. et al.Comparison of ticagrelor with clopidogrel in patients with a planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study.Lancet. 2010; 375: 283-293Abstract Full Text Full Text PDF PubMed Scopus (610) Google Scholar). In the diabetic cohort of the PLATO study, similar benefits were observed as in the overall group (40James S. Angiolillo D.J. Cornel J.H. et al.Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial.Eur Heart J. 2010; 31: 3006-3016Crossref PubMed Scopus (379) Google Scholar). The availability of more potent and reliable antiplatelet agents for the management of patients with ACS provides an opportunity to further reduce recurrent ACS and mortality. High-risk patients with diabetes with either STEMI or NSTE ACS should be considered for treatment with either prasugrel (after the coronary disease anatomy has been defined) or ticagrelor. Platelet aggregation is largely mediated by the GPIIb/IIIa receptor through its binding to fibrinogen. The GPIIb/IIIa receptor inhibitors abciximab, eptifibatide and tirofiban were shown to be effective for the management of ACS in patients with diabetes in a meta-analysis of 6 clinical trials. GPIIb/IIIa inhibitors were shown to reduce 30-day mortality by 26% (4.6% vs. 2.6%; p=0.007) (30Roffi M. Chew D.P. Mukherjee D. et al.Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes.Circulation. 2001; 104: 2767-2771Crossref PubMed Scopus (396) Google Scholar). In contrast, patients without diabetes had no mortality benefit. Although these trials were performed in an era before dual antiplatelet therapy with ASA and clopidogrel was used, recent studies indicate an additional benefit from a GPIIb/IIIa inhibitor for patients with high risk ACS, such as those with diabetes who are undergoing percutaneous coronary intervention (PCI) (41Kastrati A. Mehilli J. Neumann F.J. et al.Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial.JAMA. 2006; 295: 1531-1538Crossref PubMed Scopus (703) Google Scholar, 42De Luca G. Navarese E. Marino P. Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials.Eur Heart J. 2009; 30: 2705-2713Crossref PubMed Scopus (204) Google Scholar). Hyperglycemia during the first 24 to 48 hours after admission for ACS is associated with increased early mortality, whether or not the patient has diabetes (43Angeli F. Verdecchia P. Karthikeyan G. et al.New-onset hyperglycemia and acute coronary syndrome: a systematic overview and meta-analysis.Curr Diabetes Rev. 2010; 6: 102-110Crossref PubMed Scopus (32) Google Scholar, 44Kosiborod M. Rathore S.S. Inzucchi S.E. et al.Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: Implications for patients with and without recognized diabetes.Circulation. 2005; 111: 3078-3086Crossref PubMed Scopus (514) Google Scholar). Furthermore, in-hospital mortality has a closer relationship to hyperglycemia than to diabetic status (45Goyal A. Mehta S.R. Gerstein H.C. et al.Glucose levels compared with diabetes history in the risk assessment of patients with acute myocardial infarction.Am Heart J. 2009; 157: 763-770Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar, 46Kosiborod M. Inzucchi S.E. Krumholz H.M. et al.Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk.Circulation. 2008; 117: 1018-1027Crossref PubMed Scopus (315) Google Scholar). Higher baseline glucose and a failure of glucose to decrease are independent predictors of mortality (47Goyal A. Mahaffey K.W. Garg J. 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. 2006; 27: 1289-1297Crossref PubMed Scopus (155) Google Scholar). For patients undergoing primary angioplasty, mortality increases when the plasma glucose is >10.0 mmol/L (48Porter A. Assali A.R. Zahalka A. et al.Impaired fasting glucose and outcomes of ST-elevation acute coronary syndrome treated with primary percutaneous intervention among patients without previously known diabetes mellitus.Am Heart J. 2008; 155: 284-289Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Although elevated mean blood glucose level in the first 24 hours after onset of ACS is associated with adverse outcomes (46Kosiborod M. Inzucchi S.E. Krumholz H.M. et al.Glucometrics in patients hospitalized with acute myocardial infarction: defining the optimal outcomes-based measure of risk.Circulation. 2008; 117: 1018-1027Crossref PubMed Scopus (315) Google Scholar), evidence to support reducing blood glucose levels (especially to levels close to the normal range) after ACS remains inconclusive. The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) study indicated that tight glycemic control with the use of intravenous insulin in the early hours after presentation, followed by multidose subcutaneous insulin treatment over the subsequent months, resulted in a 30% reduction in 1-year mortality (49Malmberg K. Ryden L. Wedel H. et al.for the DIGAMI 2 Investigators Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity.Eur Heart J. 2005; 26: 650-661Crossref PubMed Scopus (681) Google Scholar, 50Malmberg K. Ryden L. Efendic S. et al.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: 57-65Abstract Full Text PDF PubMed Scopus (1382) Google Scholar, 51Malmberg K. Ryden L. Hamsten A. et al.Effects of insulin treatment on cause-specific one-ye