Management of Acute Coronary Syndromes

Canadian Diabetes Association Clinical Practice Guidelines Expert Committee

Jean-Claude Tardif MD, FRCPC, FACC, FCAHS Phillipe L. L'Allier MD David H. Fitchett MD, FRCPC

  • Key Messages
  • Recommendations
  • Figures
  • Full Text
  • References

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.

Incidence and Prognosis

Diabetes (together with lipid abnormalities, smoking and hypertension) is 1 of the top 4 independent risk factors for myocardial infarction (MI) (1). Today, approximately 15% to 35% of patients admitted with an acute coronary syndrome (ACS) have known diabetes (2), and as many as another 15% have undiagnosed diabetes (3).

Compared to individuals without diabetes, patients with diabetes have:

  1. 1.A 3-fold increased risk of ACS (4),
  2. 2.Occurrence of acute coronary events 15 years earlier (4).
  3. 3.A 2-fold increased short- (5,6) and long-term mortality (5,7,8).
  4. 4.An increased incidence of post-infarction recurrent ischemic events, heart failure and cardiogenic shock (3,9).
  5. 5.A similar benefit from guideline recommended management strategies (see below.)
  6. 6.Less utilization of guideline recommended care (10–13), which may contribute to adverse outcomes in the patient with diabetes (14).

Identification of Diabetes in Patients with ACS

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 (2). More than two-thirds of patients with MI have either diabetes or impaired glucose regulation (impaired glucose tolerance and impaired fasting glucose) (15). 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 (16). 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 (3,17). 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) (18). 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 (19). 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 (20).

Management of ACS in the Patient with Diabetes

Guidelines for the management of patients with ACS have been developed by the American College of Cardiology (ACC)/American Heart Association (AHA) (21–23) and the European Society of Cardiology (24,25). 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 (26) or primary angioplasty (27) for ST-segment elevation ACS; and b) an early invasive strategy (28), the use of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel (29), and glycoprotein (GP) IIb/IIIa inhibitors in patients with non–ST-segment elevation ACS (NSTE ACS) at high risk of recurrent ischemic events (30).

A significant care gap exists for patients with diabetes not receiving guideline-recommended treatment compared to patients without diabetes (12–14,31). It is possible that underutilization of recommended treatment is 1 factor contributing to the adverse outcome of the ACS patient with diabetes.

Antiplatelet Therapy

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 (32). 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 (32).

Diabetes is associated with an increased incidence of recurrent atherothrombotic events (8), including stent thrombosis (33). 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) (34). 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 (35). 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) (29).

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 (36). In subjects with diabetes, prasugrel treatment was associated with greater platelet inhibition and fewer poor responders (37). 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 (38). 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 P2Y 12 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 (39). In the diabetic cohort of the PLATO study, similar benefits were observed as in the overall group (40).

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) (30). 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) (41,42).

Glycemic Control

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 (43,44). Furthermore, in-hospital mortality has a closer relationship to hyperglycemia than to diabetic status (45,46). Higher baseline glucose and a failure of glucose to decrease are independent predictors of mortality (47). For patients undergoing primary angioplasty, mortality increases when the plasma glucose is >10.0 mmol/L (48).

Although elevated mean blood glucose level in the first 24 hours after onset of ACS is associated with adverse outcomes (46), 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 (49–53). The DIGAMI 2 study failed to achieve the study goals, both in the number of patients recruited and in glycemic targets (54). However, despite these limitations, it did demonstrate that outcomes were closely related to glycemic control, however achieved. Studies have shown that glucose-insulin-potassium infusion in patients with AMI do not improve outcomes (55,56). However, these protocols often resulted in increased blood glucose levels and, therefore, cannot be used as evidence for outcomes associated with glycemic control. In the Hyperglycemia: Intensive Insulin Infusion in Infarction (HI-5) study of glucose and insulin in patients with AMI, patients with a blood glucose maintained at <8.0 mmol/L had lower mortality than did subjects with higher levels (57).

The AHA Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism issued a scientific statement in 2008 on hyperglycemia and ACS (58). They recommended blood glucose targets of 5.0 to 7.7 mmol/L in the intensive care unit (ICU) setting or <10.0 mmol/L in the non-ICU setting during hospitalization for ACS. More recent ACC/AHA guidelines for the management of patients with STEMI concluded that it was prudent to change the recommendation for the use of insulin to control blood glucose in STEMI from a Class I to a Class II recommendation ( Level of Evidence: B ) and recommended treatment for hyperglycemia >10.0 mmol/L while avoiding hypoglycemia (59). The Canadian Diabetes Association recommends glucose targets of 8.0 to 10.0 mmol/L in the critically ill and premeal glucose of 5.0 to 8.0 mmol/L and random glucose levels <10.0 mmol/L (See In-hospital Management of Diabetes chapter , page S77).

Post-ACS long-term glycemic control trials using agents from newer drug classes, such as dual peroxisome proliferator-activated receptor agonist, glucagon-like peptide-1 (GLP-1) receptor agonists, and acarbose, are currently under way (e.g. A Study of Aleglitazar in Patients With Type 2 Diabetes [ALECARDIO], Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 [Lixisenatide] [ELIXA], Acarbose Cardiovascular Evaluation Trial). Until results from dedicated post-ACS studies become available, results from 5 large-scale clinical trials of stable patients with type 2 diabetes, and either known or at high risk of CAD, are helpful (60–64). A recent meta-analysis of these trials suggested a 17% relative reduction in nonfatal MI (10.0 vs. 12.3 per 1000 person-years) in subjects included in the intensive glucose control group (target A1C ≤6.0% to 6.5%; median A1C during follow-up 6.6%), yet there was no reduction of all-cause mortality (65,66). The same meta-analysis indicated the possibility that a greater benefit could be derived from treating patients with recently diagnosed diabetes more intensively.

Revascularization

ACS practice guidelines promote the same treatment strategies in patients with diabetes as for those without diabetes (67). An early invasive strategy with revascularization when possible in NSTE ACS provides a similar or greater reduction in death and MI (up to 5 years of follow-up) in the subset of patients with diabetes compared to the overall population (28,68,69). The 2011 ACC AHA non-STE ACS guidelines recommend that NSTE ACS should be considered for an early invasive, rather than a selective invasive (conservative), strategy.

In patients with diabetes and NSTE ACS and multivessel disease, CABG with the use of internal mammary artery may provide benefit over PCI when revascularization is indicated (70). However, PCI (with drug-eluting stents whenever possible) is acceptable for patients with less extensive disease (i.e. single-vessel disease) (59). For patients with ST-elevation ACS, immediate reperfusion strategies with either fibrinolysis or primary PCI result in similar benefits for patients with and without diabetes. The benefits of primary PCI over fibrinolysis in patients with diabetes are similar to those without diabetes (mortality with primary PCI vs. fibrinolysis in patients with diabetes, odds ratio (OR) 0.49, 95% CI 0.31–0.79) (27). However, fibrinolysis should be administered when primary PCI is not available within acceptable timeframes. Ocular hemorrhage in patients with diabetic retinopathy is extremely rare and should not limit the use of fibrinolysis when it is indicated (71).

Recommendations

  1. 1.Patients with ACS should be screened for diabetes with a fasting blood glucose, A1C or 75 g OGTT prior to discharge from hospital [Grade D, Consensus].
  2. 2.All patients with diabetes and ACS should receive the same treatments that are recommended for patients with ACS without diabetes since they benefit equally [Grade D, Consensus].
  3. 3.Patients with diabetes and ACS undergoing PCI should receive antiplatelet therapy with prasugrel (if clopidogrel naïve, <75 years of age, weight >65 kg, and no history of stroke) [Grade A, Level 1 (36,38) ] or ticagrelor [Grade B, Level 1 (39,40) ], rather than clopidogrel, to further reduce recurrent ischemic events. Patients with diabetes and non-STE ACS and higher-risk features destined for a selective invasive strategy should receive ticagrelor rather than clopidogrel [Grade B, Level 2 (39,40)].
  4. 4.Patients with diabetes and non-STE ACS and high-risk features should receive an early invasive strategy rather than a selective invasive approach to revascularization to reduce recurrent coronary events, unless contraindicated [Grade B, Level 2 (28) ].
  5. 5.In patients with diabetes and STE ACS, the presence of retinopathy should not be a contraindication to fibrinolysis [Grade B, Level 2 (71) ].
  6. 6.In-hospital management of diabetes in ACS should include strategies to avoid both hyperglycemia and hypoglycemia:
    • Blood glucose should be measured on admission and monitored throughout the hospitalization [Grade D, Consensus]
    • Patients with acute MI and blood glucose >11.0 mmol/L on admission may receive glycemic control in the range of 7.0 to 10.0 mmol/L, followed by strategies to achieve recommended glucose targets long term [Grade C, Level 2 (52,54) ]. Insulin therapy may be required to achieve these targets [Grade D, Consensus]. A similar approach may be taken in those with diabetes and admission blood glucose ≤11.0 mmol/L [Grade D, Consensus] (see In-hospital chapter, p. S77).
    • An appropriate protocol should be developed and staff trained to ensure the safe and effective implementation of this therapy and to minimize the likelihood of hypoglycemia [Grade D, Consensus].

Abbreviations:
A1C, glycated hemoglobin; ACS, acute coronary syndrome; OGTT, oral glucose tolerance test; PCI, percutaneous coronary intervention; STE, ST elevation.

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