Management of Acute Coronary Syndromes

Abstract

Key Messages•Over the past 20 years, the rates of acute myocardial infarction in people with diabetes has decreased substantially. However, the burden of disease remains high because of the increased prevalence of diabetes.•Diabetes and hyperglycemia are independent predictors of increased short- and long-term mortality, recurrent myocardial infarction, and the development of heart failure in patients with acute myocardial infarction.•People with an acute myocardial infarction and hyperglycemia (random blood glucose >11.0 mmol/L) may receive antihyperglycemic therapy to maintain blood glucose levels between 7.0 to 10.0 mmol/L.•People with diabetes are less likely to receive recommended treatment, such as an early invasive strategy and revascularization, reperfusion therapy, beta blockers or dual antiplatelet therapy than people without diabetes. Efforts should be directed at promoting adherence to existing proven therapies in the high-risk person with myocardial infarction and diabetes.Key Messages for People with Diabetes•A heart attack can manifest as chest discomfort or crushing pain; or as pain in the arms, back, neck, jaw and, even, the stomach. Shortness of breath, cold sweat, nausea and lightheadedness may also occur.•If you are experiencing symptoms of a heart attack, you should seek medical help immediately. The faster treatment is started, the better. •Over the past 20 years, the rates of acute myocardial infarction in people with diabetes has decreased substantially. However, the burden of disease remains high because of the increased prevalence of diabetes.•Diabetes and hyperglycemia are independent predictors of increased short- and long-term mortality, recurrent myocardial infarction, and the development of heart failure in patients with acute myocardial infarction.•People with an acute myocardial infarction and hyperglycemia (random blood glucose >11.0 mmol/L) may receive antihyperglycemic therapy to maintain blood glucose levels between 7.0 to 10.0 mmol/L.•People with diabetes are less likely to receive recommended treatment, such as an early invasive strategy and revascularization, reperfusion therapy, beta blockers or dual antiplatelet therapy than people without diabetes. Efforts should be directed at promoting adherence to existing proven therapies in the high-risk person with myocardial infarction and diabetes. •A heart attack can manifest as chest discomfort or crushing pain; or as pain in the arms, back, neck, jaw and, even, the stomach. Shortness of breath, cold sweat, nausea and lightheadedness may also occur.•If you are experiencing symptoms of a heart attack, you should seek medical help immediately. The faster treatment is started, the better. Diabetes (together with lipid abnormalities, smoking and hypertension) is one 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 (8412) Google Scholar). Today, approximately 15% to 35% of people 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; 2011: 145615Crossref PubMed Scopus (21) Google Scholar), and as many as a further 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). Between 1990 and 2010, there was a 67.8% reduction of the rates of acute MI in people with diabetes, compared to a 32% reduction in individuals without diabetes (4Gregg E.W. Li Y. Wang J. et al.Changes in diabetes-related complications in the United States, 1990–2010.N Engl J Med. 2014; 370: 1514-1523Crossref PubMed Scopus (1155) Google Scholar). However, as a result of the substantial increase in the prevalence of diabetes over this period, the public health burden of MI in people with diabetes continues to rise. Compared to individuals without diabetes, people with diabetes have:•A 3-fold increased risk of ACS (5Booth G.L. Kapral M.K. Fung K. et al.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 (539) Google Scholar)•Occurrence of acute coronary events 15 years earlier (5Booth G.L. Kapral M.K. Fung K. et al.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 (539) Google Scholar)•A 2-fold increased short- (6Donahoe S.M. Stewart G.C. McCabe C.H. et al.Diabetes and mortality following acute coronary syndromes.JAMA. 2007; 298: 765-775Crossref PubMed Scopus (541) Google Scholar, 7Behar S. Boyko V. Reicher-Reiss H. et al.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 (6Donahoe S.M. Stewart G.C. McCabe C.H. et al.Diabetes and mortality following acute coronary syndromes.JAMA. 2007; 298: 765-775Crossref PubMed Scopus (541) Google Scholar, 8Kumler T. Gislason G.H. Kober L. et al.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)•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)•A similar benefit from guideline-recommended management strategies (see below)•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.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 (59) Google Scholar), including an invasive strategy (14Gustafsson I. Hvelplund A. Hansen K.W. et al.Underuse of an invasive strategy for patients with diabetes with acute coronary syndrome: A nationwide study.Open Heart. 2015; 2: e000165Crossref PubMed Google Scholar) which may contribute to adverse outcomes (15Yan R.T. Yan A.T. Tan M. et al.Underuse of evidence-based treatment partly explains the worse clinical outcome in diabetic patients with acute coronary syndromes.Am Heart J. 2006; 152: 676-683Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). It is recognized that there is a wide range of risk for an adverse outcome in people with diabetes after an ACS. A recent study developed a prediction model that indicated age, renal dysfunction, the presence of anemia, heart failure or left ventricular (LV) dysfunction, in-hospital revascularization, obesity, prior ACS and insulin treatment were factors significantly associated with mortality during the 5 years after acute MI (AMI) (16Arnold S.V. Spertus J.A. Jones P.G. et al.Predicting adverse outcomes after myocardial infarction among patients with diabetes mellitus.Circ Cardiovasc Qual Outcomes. 2016; 9: 372-379Crossref PubMed Scopus (23) Google Scholar). Although the absolute number of people 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 (16Arnold S.V. Spertus J.A. Jones P.G. et al.Predicting adverse outcomes after myocardial infarction among patients with diabetes mellitus.Circ Cardiovasc Qual Outcomes. 2016; 9: 372-379Crossref PubMed Scopus (23) Google Scholar). More than two-thirds of people with MI have either diabetes or prediabetes (impaired glucose tolerance [IGT] or impaired fasting glucose [IFG]) (17Bartnik 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 people with MI compared to a matched control population and is a marker for adverse outcomes (18Bartnik 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, 19Mozaffarian 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 (130) Google Scholar). If fasting plasma glucose (FPG) 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) (20Bartnik 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). An A1C >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 (see Screening for Diabetes in Adults chapter, p. S16). One study has validated the use of A1C in an acute care population and found that using the 2-hour 75 g 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% (21Silverman 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). It is accepted that some people with diabetes will be missed by screening with fasting plasma glucose (FPG) and A1C compared to the universal use of an OGTT. However, it is likely that the people most in need of glycemic control will be detected with these simple tests that can be widely applied. In-hospital capillary blood glucose monitoring should be started in individuals without a history of diabetes with an admission A1C ≥6.5% or random plasma glucose (PG) >10.0 mmol/L. Individuals with an A1C between 5.5% to 6.4% should have repeat screening after discharge as per diabetes screening guidelines (see Screening for Diabetes in Adults chapter, p. S16 and Figure 1). Guidelines for the management of people with ACS have been developed by the American College of Cardiology/American Heart Association (22Anderson 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: 652-726Crossref Scopus (240) Google Scholar, 23Kushner F.G. Hand M. Smith Jr, S.C. et al.2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American college of cardiology foundation/American heart association task force on practice guidelines.J Am Coll Cardiol. 2009; 54: 2205-2241Crossref PubMed Scopus (1157) Google Scholar, 24Wright R.S. Anderson J.L. Adams C.D. et al.2011 ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial Infarction (updating the 2007 guideline): A report of the American college of cardiology foundation/American heart association task force on practice guidelines developed in collaboration with the American college of emergency physicians, society for cardiovascular angiography and interventions, and society of thoracic surgeons.J Am Coll Cardiol. 2011; 57: 1920-1959Crossref PubMed Scopus (323) Google Scholar) and the European Society of Cardiology (25Van de Werf F. Bax J. Betriu A. et al.Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: The task force on the management of ST-segment elevation acute myocardial infarction of the European society of cardiology.Eur Heart J. 2008; 29: 2909-2945Crossref PubMed Scopus (1) Google Scholar, 26Bassand J.P. Hamm C.W. et al.Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of CardiologyGuidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes.Eur Heart J. 2007; 28: 1598-1660Crossref PubMed Scopus (1) Google Scholar). In most situations, there are no clinical trials that specifically address management of people with diabetes and ACS; however, subgroup analyses in people with diabetes and ACS show either a similar or enhanced benefit from treatment compared to the overall group for: a) reperfusion with fibrinolysis (27Fibrinolytic 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 (2814) Google Scholar) or primary angioplasty (28Timmer J.R. van der Horst I.C. de Luca G. 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 (29O'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: 106-111Crossref PubMed Scopus (63) Google Scholar) with the use of dual anti-platelet therapy with acetylsalicylic acid (ASA) and clopidogrel (30Yusuf 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 (6037) Google Scholar), glycoprotein IIb/IIIa inhibitors and the newer P2Y12 platelet inhibitors (prasugrel and ticagrelor) in people with non-ST segment elevation ACS at high risk of recurrent ischemic events (31Roffi 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 (394) Google Scholar). A significant care gap exists for people with diabetes not receiving guideline-recommended treatment compared to people without diabetes (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.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, 15Yan R.T. Yan A.T. Tan M. et al.Underuse of evidence-based treatment partly explains the worse clinical outcome in diabetic patients with acute coronary syndromes.Am Heart J. 2006; 152: 676-683Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 16Arnold S.V. Spertus J.A. Jones P.G. et al.Predicting adverse outcomes after myocardial infarction among patients with diabetes mellitus.Circ Cardiovasc Qual Outcomes. 2016; 9: 372-379Crossref PubMed Scopus (23) Google Scholar). It is possible that the underutilization of recommended treatment is one factor contributing to the adverse outcome of the person with diabetes and ACS. Platelet aggregation plays a central role in the development of the occlusive thrombus responsible for acute coronary occlusion in people with ACS. People with diabetes have a pro-thrombotic 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 (252) 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 (252) Google Scholar). Diabetes is associated with an increased incidence of recurrent atherothrombotic events (33Malmberg 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 (652) Google Scholar), including stent thrombosis (34Iakovou 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 (2933) Google Scholar). Anti-platelet therapy has been shown to reduce atherothrombotic events in people 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 non–ST-segment elevation acute coronary syndrome (NSTE ACS) and ST-segment elevation MI (STEMI). The Antithrombotic Trialist's Collaboration meta-analysis (35Antithrombotic 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) of anti-platelet therapy (mainly ASA) included 212,000 high-risk participants (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 the participants with diabetes (22.3% to 18.5%; p<0.002). Low-dose ASA (75 to 150 mg) was as effective as higher doses (>150 mg) with a lower incidence of bleeding complications. The Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes (CURRENT/OASIS 7) trial (36Mehta 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 (738) Google Scholar) also was unable to show any benefit from higher dose compared to low-dose (75 to 100 mg) ASA in people with and without diabetes. The use of low-dose ASA is recommended to minimize GI bleeding in people with and without diabetes (see Cardiovascular Protection in People with Diabetes chapter, p. S162). Dual anti-platelet therapy with ASA and clopidogrel, administered from the time of presentation, has been the recommended standard of care for people with NSTE ACS. People with diabetes in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial (30Yusuf 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 (6037) Google Scholar) had a similar benefit with clopidogrel vs. placebo (14.2% vs. 17.7%, RR 0.84, 95% CI 0.70–1.02) as the overall population (9.3% vs. 11.4%, RR 0.80, 95% CI 0.72–0.90). Despite dual-antiplatelet therapy with ASA and clopidogrel, recurrent atherothrombotic events continue to occur, especially in the person 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 people with residual platelet activity and people with diabetes have higher residual platelet activity despite ASA and clopidogrel treatment. Two more potent antiplatelet agents, prasugrel and ticagrelor, that are more effective and predictable inhibitors of platelet aggregation, have been shown to improve outcomes, especially in people with diabetes. In the TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel - Thrombolysis In Myocardial Infarction (TRITON-TIMI 38) trial, prasugrel administered at the time of coronary angioplasty in participants with ACS reduced recurrent ischemic events, including stent thrombosis, compared to participants receiving clopidogrel (37Wiviott S.D. Braunwald E. McCabe C.H. et al.Prasugrel versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2007; 357: 2001-2015Crossref PubMed Scopus (5543) Google Scholar). In subjects with diabetes, prasugrel treatment was associated with greater platelet inhibition and fewer poor responders (38Angiolillo 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 (171) Google Scholar). Prasugrel resulted in an important net clinical benefit in people with diabetes (39Wiviott S.D. Braunwald E. Angiolillo D.J. et al.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 (682) Google Scholar) (14.6 vs. 19.2%, HR 0.74, p=0.001) due to a 30% reduction of the primary endpoint (cardiovascular [CV]) death, non-fatal MI or stroke over the 14.4 months of the study. 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 people with diabetes. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, the P2Y12 receptor antagonist ticagrelor, when compared with clopidogrel and administered early after presentation in people with NSTE ACS or STEMI, reduced CV death, non-fatal 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 people not undergoing coronary bypass surgery (40Cannon 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 (609) Google Scholar). In the diabetic cohort of the PLATO study, similar benefits were observed as in the overall group (41James 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 (377) Google Scholar). The availability of more potent and reliable anti-platelet agents for the management of people with ACS provides an opportunity to further reduce recurrent ACS and mortality. High-risk people 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 glycoprotein (GP) IIb/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 people 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) (31Roffi 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 (394) Google Scholar). In contrast, people without diabetes had no mortality benefit. Although these trials were performed in an era before dual anti-platelet therapy with ASA and clopidogrel was used, studies (42Kastrati 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 (700) Google Scholar, 43De 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 (203) Google Scholar) indicate an additional benefit from a GPIIb/IIIa inhibitor for people with high-risk ACS, such as those with diabetes who are undergoing percutaneous coronary intervention (PCI). However, these benefits have not been observed when more potent oral anti-platelet agents, such as ticagrelor, are used (44Wallentin L. Becker R.C. Budaj A. et al.Ticagrelor versus clopidogrel in patients with acute coronary syndromes.N Engl J Med. 2009; 361: 1045-1057Crossref PubMed Scopus (5522) Google Scholar). More prolonged duration dual anti-platelet therapy with ASA and ticagrelor in people with ACS, administered for up to 3 years beyond the usual 1-year treatment, was shown in the Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial to reduce t