19.6 Special conditions: acute coronary syndromes

Diabetes is a major risk factor for cardiovascular disease and is associated with an increased risk of mortality in the setting of acute coronary syndromes. Like patients without diabetes, ST elevation and non-ST elevation myocardial infarction patients mandate immediate and within 24 h coronary angiography, respectively. Even in the absence of troponin elevation, all patients with diabetes with suspected acute coronary syndromes should undergo coronary angiography within 72 h due to their increased risk (which is not the case for individuals without diabetes). Antiplatelet treatment should be handled as in patients without diabetes, and the more potent P2Y₁₂ inhibitors prasugrel and ticagrelor should be preferred over clopidogrel. Overall, trials investigating the impact of intensive glucose-lowering therapies in the acute phase of acute coronary syndromes did not show a positive impact on clinical outcomes. In the long term, efforts in secondary prevention to reach recommended global preventive targets are especially important in this patient population to improve survival and reduce the recurrence of ischaemic events.

Diabetes mellitus is characterized by a chronic hyperglycaemic state resulting from insulin resistance and impairment of both secretion and action of insulin (see Chapter 19.2).¹ The diagnosis is usually established before the diagnosis of cardiovascular disease (CVD) or at the time of screening for risk factors in patients with an acute cardiovascular event, such as ACS (see Section 29).¹ There is no well-accepted definition of hyperglycaemia in the context of ACS. The American Heart Association guidelines defined hyperglycaemia as a random plasma glucose value of greater than 140 mg/dL (7.8 mmol/L) during index hospitalization for both diabetic and non-diabetic patients, while the European Society of Cardiology (ESC) Guidelines define hyperglycaemia requiring therapy as any value greater than 10 mmol/L (>180 mg/dL).^2,3

Screening for diabetes mellitus is mandatory in all ACS patients,³ as more than half of them may have undiagnosed diabetes (see Chapter 19.2).^4,5 Glycated haemoglobin (HbA_1c) and fasting plasma glucose are the mainstays in the diagnosis of diabetes mellitus, while an oral glucose tolerance test is rarely performed in the internal medicine or cardiology setting.⁶ According to the ESC Guidelines for diabetes management, the diagnosis of diabetes mellitus in stable patients is defined by any of the following: fasting plasma glucose of at least 7.0 mmol/L, plasma glucose 2h following oral glucose tolerance test of at least 11.1 mmol/L, or HbA1c level of at least 6.5%.¹ Any abnormal values should be repeated to confirm the diagnosis.^2,3

Several studies have shown that ACS patients with diabetes, those with previously undiagnosed diabetes, or those with hyperglycaemia at presentation have an increased mortality as compared with individuals with normal plasma glucose levels.^7,8 In a study including 62,036 patients, the presence of diabetes in the context of ACS was associated with higher risk for 30-day mortality (odds ratio (OR) 1.78; 95% confidence interval (CI) 1.24–2.56) and 1-year mortality (hazard ratio (HR) 0.165; 95% CI 1.30–2.10).⁹ In the Swiss Acute Myocardial Infarction in Switzerland (AMIS) registry including 3565 patients with and 15,531 without diabetes, the in-hospital mortality was twofold higher (12.1% vs 6.1%; p <0.001) in those with diabetes compared to those without it.¹⁰ Notably, in this study the mortality decreased significantly over time also in patients with diabetes, from 19.9% in 1997 to 9.0% in 2010. Among people with diabetes, women had a higher mortality than men (16.1 vs 10.2%; p <0.001).¹⁰ In an registry of 11,232 patients with myocardial infarction in the United States, the overall mortality after a follow-up of 3.5 years was significantly higher in patients with diabetes (relative risk (RR) 1.68; 95% CI 1.44–1.95; p <0.001) compared with individuals without diabetes; the same was true for major cardiovascular events (RR 1.47; 95% CI 1.27–1.70) and heart failure (RR 1.89; 95% CI 1.34–2.67).¹¹ Among 8795 patients with non-ST elevation myocardial infarction (NSTEMI) enrolled in the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, the presence of unknown diabetes was associated with a higher risk of 30-day mortality (OR 1.65; 95% CI 1.09–2.48) to a similar degree as those with previously known diabetes (OR 1.40; 95% CI 1.01–1.93).⁸ In a large registry of 141,680 elderly patients without known diabetes mellitus hospitalized for myocardial infarction, elevated glucose levels at hospital admission were associated with a higher risk of 30-day mortality. Compared with patients with a glucose less than or equal to 110 mg/dL (6.1 mmol/L), the HR was 1.17 (95% CI 1.11–1.24) for glucose between 110 and 140 mg/dL (6.1 and 78 mmol/L) and the HR was 1.87 (95% CI 1.75–2.00) for glucose greater than 240 mg/dL (13.3 mmol/L).¹² Interestingly, the risk of mortality in the study was significantly higher in patients undiagnosed with diabetes mellitus compared with those with known diabetes mellitus (p-value for interaction <0.001).

Mechanistic studies suggest that hyperglycaemia increases vascular inflammation, atherosclerosis, and the probability of plaque rupture (see Chapter 19.3).¹³ All ACS patients with ST elevation myocardial infarction (STEMI) or haemodynamic instability require immediate (i.e. <2 h) reperfusion. The 2015 ESC Guidelines for non-ST-elevation (NSTE)-ACS recommend an early invasive strategy (i.e. <24 h) for all NSTEMI patients, as well as for patients with dynamic ST- or- T-wave changes or GRACE score greater than 140 points.³ Of note, neither fasting plasma glucose nor diabetes status are included in the GRACE score. In the absence of troponin elevation or with troponin levels in the ‘grey zone’ (i.e. neither rule in nor rule out myocardial infarction), diabetes mellitus per se is considered an intermediate-risk criterion in the context of suspected ACS and mandates, according to the most recent ESC NSTE-ACS guidelines, coronary angiography within 72 h of hospital admission. In patients undergoing percutaneous coronary intervention (PCI), the use of drug-eluting stents has decreased the relative risk of in-stent restenosis by 70–80%, and as a consequence, of repeat revascularization, compared to that observed with bare-metal stents.¹⁴ As patients with diabetes are characterized by an increased risk of restenosis, the impact of drug-eluting stents has been spectacular in this patient population. In addition, the use of new-generation drug-eluting stents has significantly reduced the risk of late stent thrombosis observed with first-generation devices.^14,15 This development was of particular importance in patients with diabetes, as in multiple studies with first-generation devices, diabetes was identified as an independent predictor of stent thrombosis.¹⁶

Controversy persists as to the optimal revascularization strategy for patients with diabetes with multivessel coronary artery disease (CAD) presenting with ACS, as no randomized controlled trial has compared PCI versus coronary artery bypass grafting (CABG) in this setting (Figure 19.6.1). Therefore, evidence is extrapolated from randomized controlled trials performed in patients with stable CAD. While STEMI patients almost invariably undergo PCI, in the setting of NSTE-ACS the decision for the optimal revascularization strategy should be based on clinical presentation as well as the pattern and complexity of coronary disease (e.g. SYNTAX score), accessibility of the coronary lesions for PCI, suitability of distal segments for bypass grafting, ischaemic burden, cardiac function, and co-morbidities (e.g. STS score; see Chapter 31.12).³ Based on randomized controlled trials enrolling exclusively diabetic patients or subgroup analyses of populations with diabetes within randomized controlled trials, patients with stabilized multivessel CAD and an acceptable surgical risk, CABG is recommended over PCI.^17,18,19 For those who have less complex multivessel disease (SYNTAX score ≤22 points), PCI is a recommended alternative strategy to CABG.³ All stabilized patients with diabetes and complex multivessel disease should be discussed within the Heart Team to select the optimal revascularization treatment (Figure 19.6.2; see Chapter 58.2). The threshold for CABG should be lower in patients with diabetes compared with those free from diabetes. In patients with diabetes and ongoing ischaemia or haemodynamic instability, immediate coronary angiography (<2 h) is recommended and the best revascularization should be chosen on a case-by-case basis taking into account the increased risk of performing CABG in the setting of ongoing ischemia.¹⁶ It is recommended to monitor renal function for 2–3 days after coronary angiography or PCI in patients with baseline renal impairment or those on metformin.^1,3 If renal functional deteriorates in patients on metformin, it is recommended to withhold the drug until renal function returned to its initial level.¹

Data regarding optimal dual antiplatelet therapy (i.e. aspirin and a P2Y₁₂ inhibitor) in patients with diabetes is derived from subgroup analyses of randomized controlled trials enrolling both STEMI and NSTE-ACS patients (see Chapter 5.7). In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) trial, among 3146 patients with diabetes a significant reduction in the composite endpoint of cardiovascular death, infarction, and cerebrovascular events at a follow-up of up to 15 months was observed in patients allocated to prasugrel as compared with clopidogrel (12.2% vs 17.0%; HR 0.70; 95% CI 0.58–0.85; p <0.001). The benefit was even more pronounced among the 776 patients with diabetes treated with insulin (14.3% vs 22.2%; HR 0.63; 95% CI 0.44–0.89 (p = 0.009).²⁰ Surprisingly, the TIMI major bleeding rates were similar in patients with diabetes mellitus for both clopidogrel and prasugrel (2.6% and 2.5%, respectively). In the Platelet Inhibition and Patient Outcomes (PLATO) trial, the 4662 patients with diabetes derived a similar benefit as the overall trial population from ticagrelor as compared with clopidogrel as regards the primary composite endpoint of cardiovascular death, infarction, or stroke at 12 months (HR 0.88; 95% CI 0.76–1.03). However, ticagrelor treatment was associated with an increase in non-CABG major bleedings (HR 1.38; 95% CI 1.17–1.62; p <0.001).²¹ As a general rule, it is recommended to administer the same antiplatelet treatment to individuals with and without diabetes (see Chapter 29.6). In addition to aspirin, ticagrelor regardless of the revascularization strategy or prasugrel (at the time of PCI) is recommended for 12 months in the absence of contraindications. Clopidogrel is reserved for patients at high bleeding risk or for those who require oral anticoagulation.

The impact of aggressive glucose-lowering strategies in ACS has been tested mainly in patients with STEMI, with controversial results (see Chapters 5.10 and 19.5).²² In the Diabetes Mellitus Insulin-Glucose In Acute Myocardial Infarction (DIGAMI)-I trial, including 620 patients with diabetes with hyperglycaemia of greater than 11 mmol/L (198 mg/dL), an insulin-based glucose-lowering treatment was superior in terms of 1-year mortality compared with standard care (18.6% vs 26.1%; p = 0.027).²³ In the DIGAMI-2 trial, 1253 diabetic patients were randomized to an intense short-term (intravenous dextrose–insulin infusion) plus long-term (subcutaneous insulin injection) treatment regimen versus usual care. There was no significant difference in the primary endpoint of all-cause mortality after a mean follow-up of 2 years.²⁴ In the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation-Estudios Cardiologicas Latin America Study Group (CREATE-ECLA) trial, enrolling 20,021 patients without diabetes with STEMI, the addition of glucose–insulin–potassium infusion did not impact mortality.²⁵ In the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) trial enrolling 852 patients, glucose–insulin–potassium infusion was tested against placebo in 442 ACS patients.²⁶ The study medication was started by paramedics of the out-of-hospital emergency medical services and continued for 12 h. The primary endpoint was progression of ACS to myocardial infarction within 24 h, while prespecified secondary endpoints were pre- or in-hospital cardiac arrest. No significant differences were found for progression to infarction (48.7% vs 52.6%; OR 0.88; 95% CI 0.66–1.13; p = 0.28). However, glucose–insulin–potassium infusion was associated with a significant 52% reduction in cardiac arrest and in-hospital mortality (4.4% vs 8.7%; OR 0.48; 95% CI 0.27–0.85; p =0.01).²⁶ In the BIOMarker Study to Identify the Acute Risk of a Coronary Syndrome-2 (BIOMArCS-2) study, the authors tested the infusion of insulin to restore normoglycaemia in ACS patients with an admission glucose between 140 mg/dL (12.8mmol/L) and 288 mg/dL (25 mmol/L). The primary endpoint was the concentration of high-sensitivity troponin 72 h after admission. The infusion of insulin 5 h after symptom onset and 2.3 h after PCI did not significantly reduce the 72 h troponin or creatinine kinase levels, but showed a trend towards a reduction of infarct size at 6 month (p = 0.07). However, in the insulin infusion group an increased risk of in-hospital death or spontaneous second myocardial infarction was observed (p = 0.04).²⁷ According to the 2015 ESC NSTE-ACS guidelines, glucose-lowering therapy should be considered in ACS patients with blood glucose greater than 10 mmol/L (>180 mg/dL) with the target adapted to co-morbidities (e.g. less stringent targets in the elderly or in patients with long-standing diabetes or multiple co-morbidities), while episodes of hypoglycaemia should be avoided.³ However, the long-term CVD impact of most glucose-lowering treatments remains unknown. The recently published Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME^®) demonstrated for the first time in 7020 diabetic patients at high risk of cardiovascular events a reduction of the primary outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke at 3 years with the sodium–glucose cotransporter inhibitor empagliflozin compared to placebo (10.5% vs 12.1%; HR 0.86; 95% CI 0.74–0.99; p = 0.04).²⁸ However, recent (i.e. within 2 months) ACS was an exclusion criteria of the study. The impact of hypoglycaemia on mortality in ACS represents a major gap in knowledge.^1,22

As recently observed in a Swedish ACS registry including 108,315 patients, diabetes remains an independent risk factor of long-term cardiovascular events.²⁹ All patients with diabetes have to be screened for hyperlipidaemia, hypertension, smoking, poor physical activity, overweight, and inappropriate dietary habits.¹ Patients with diabetes are at very high risk of additional macrovascular (i.e. CAD, peripheral artery disease, or cerebrovascular events) and microvascular (i.e. retinopathy, nephropathy, or neuropathy) diseases. In addition, diabetic patients with CAD have a higher prevalence of heart failure, atrial fibrillation, and renal dysfunction.¹

Patients with long-standing diabetes mellitus need additional screening for end-organ damage and consultation by a diabetologist. Multifactorial and multidisciplinary management include patient education and empowerment, lifestyle counselling (e.g. smoking cessation, education on the importance of physical activity as well as weight reduction, and diet counselling) and pharmacological treatment to reach recommended targets of blood pressure, lipids, and glucose. Less stringent glucose control should be considered in the elderly as well as in patients with co-morbidities and long diabetes duration.³⁰ The clinical relevance of the metabolic side effects of beta blockers or diuretics is still a source of debate. The key targets for prevention and medical management are summarized in Table 19.6.1. For that purpose, participation in a cardiac rehabilitation programme is strongly recommended in all ACS patients, and especially, in diabetic individuals.