**7.1. Cardiac rhythm monitoring**

Early revascularization, effective antithrombotic therapy and administration of beta-blockers have reduced the incidence of life threatening arrhythmias in the acute phase of MI to <3%, with most of the arrhythmic events occurring within 12 h of symptom onset [72, 73]. Patients with life-threatening arrhythmias frequently had prior heart failure, low LV ejection fraction (EF < 30%) and triple vessel CAD.

NSTEMI patients at low risk for cardiac arrhythmias require rhythm monitoring for ≤24 h or until coronary revascularization (whichever comes first) in an intermediate or coronary care unit, while individuals at intermediate to high risk for cardiac arrhythmia may require rhythm monitoring for >24 h in an intensive or coronary care unit or in an intermediate care unit, depending on the clinical presentation, degree of revascularization and early post-revascularization course.

All patients require oxygen saturation measurement using pulse oximetry [1]. Although in the past oxygen was routinely given to all patients, there is no evidence to support this practice [74]. Moreover, results of the Air Versus Oxygen in ST-elevation MyocarDial Infarction (AVOID) trial have shown that routine supplemental oxygen may increase myocardial infarct size, and raise rates of recurrent MI and cardiac arrhythmia in patients with ST-elevation MI but without hypoxia. Guidelines now recommend supplemental oxygen therapy only in patients who are hypoxemic (arterial oxygen saturation < 90%), or in those who have respiratory distress or other high-risk features for hypoxemia [1, 15, 75].

### **7.2. Pharmacological treatment of ischemia**

while in hospital, at 6 months, at 1 year and at 3 years. The combined risk of death or MI at 1 year is also provided [70]. Variables used in the GRACE 2.0 risk calculation include age, systolic blood pressure, pulse rate, serum creatinine, Killip class at presentation, cardiac arrest at admission, elevated cardiac biomarkers and ST deviation. The TIMI risk score uses seven variables in an additive scoring system: age ≥ 65 years, three or more CAD risk factors, known CAD, aspirin use in the past 7 days, severe angina (two or more episodes within 24 h), ST change ≥0.5 mm and positive cardiac marker [71]. Patients with a TIMI score of 0–2 are low risk, 3–4 are intermediate risk, and 5–7 are high risk. All-cause mortality, rate of MI, and rate of urgent revascularization at 14 days increase in proportion to the number of risk factors present on the TIMI score. It is simple

to use, but its discriminative accuracy is inferior to that of the GRACE risk score [1, 71].

The aim of initial evaluation is to relieve pain and ischemia, prevent further thrombosis or embolism, and correct hemodynamic abnormalities and treat life-threatening complication. All patients should undergo early risk estimation based on the medical history, physical

Initial medical therapy is indicated in all patients, with variation in some choices of agent

Early revascularization, effective antithrombotic therapy and administration of beta-blockers have reduced the incidence of life threatening arrhythmias in the acute phase of MI to <3%, with most of the arrhythmic events occurring within 12 h of symptom onset [72, 73]. Patients with life-threatening arrhythmias frequently had prior heart failure, low LV ejection fraction

NSTEMI patients at low risk for cardiac arrhythmias require rhythm monitoring for ≤24 h or until coronary revascularization (whichever comes first) in an intermediate or coronary care unit, while individuals at intermediate to high risk for cardiac arrhythmia may require rhythm monitoring for >24 h in an intensive or coronary care unit or in an intermediate care unit, depending on the clinical presentation, degree of revascularization and early post-revascularization course. All patients require oxygen saturation measurement using pulse oximetry [1]. Although in the past oxygen was routinely given to all patients, there is no evidence to support this practice [74]. Moreover, results of the Air Versus Oxygen in ST-elevation MyocarDial Infarction (AVOID) trial have shown that routine supplemental oxygen may increase myocardial infarct size, and raise rates of recurrent MI and cardiac arrhythmia in patients with ST-elevation

**6. Hospital care and standard medical therapies**

exam, ECG findings, and cardiac markers.

**7. Initial management**

70 Myocardial Infarction

according to risk stratification.

**7.1. Cardiac rhythm monitoring**

(EF < 30%) and triple vessel CAD.

The goal of pharmacological anti-ischemic therapy is to decrease myocardial oxygen demand (secondary to a decrease in heart rate, blood pressure, preload or myocardial contractility) or to increase myocardial oxygen supply (by administration of oxygen or through coronary vasodilation).

Pain relief is indicated in the initial management of all patients. Those with ongoing ischemic discomfort should receive a trial of sublingual nitroglycerin (0. 4 mg) every 5 min for a total of three doses. Sublingual nitroglycerin reduces myocardial oxygen demand and enhances myocardial oxygen delivery. Intravenous nitroglycerin is recommended in patients with no symptom relief after sublingual nitroglycerin. Under careful blood pressure monitoring, the dose should be titrated upwards until symptoms are relieved, and in hypertensive patients until blood pressure is normalized, unless side effects (notably headache or hypotension) occur. Beyond symptom control, there is no indication for nitrate treatment [76]. In patients with recent intake of a phosphodiesterase type 5 inhibitor (i.e. within 24 h for sildenafil or vardenafil and 48 h for tadalafil), nitrates should not be administered due to the risk of severe hypotension. Nitroglycerin should not be given if systolic BP is <90 mmHg or there is a concern about right ventricular infarction [77]. If the patient does not respond to nitroglycerin, intravenous morphine can be administered in the absence of any contraindications [1]. Morphine causes vasodilation and may produce reductions in heart rate (through increased vagal tone) and systolic BP to further reduce myocardial oxygen demand. It should be given instead of nitroglycerin when nitroglycerin is contraindicated. Morphine should be used with caution, one randomized, double-blind trial found that morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction [78, 79].

#### *7.2.1. Beta-blockers*

Oral beta-blockers are recommended for routine use in all patients unless contraindicated. Beta-blockers competitively inhibit the myocardial effects of circulating catecholamines and reduce myocardial oxygen consumption by lowering heart rate, blood pressure and myocardial contractility. Randomized trials with threatened or evolving MI have shown lower rates of progression to MI with beta-blocker treatment [80].

The beneficial effects of beta-blockers derived from several meta-analyses were a significant 8 and 13% relative risk reduction for in-hospital and first week mortality following MI respectively with no increase in cardiogenic shock [81, 82].

A registry study of NSTEMI patients found that the use of B-Blocker blockers within 24 h of hospital admission in patients at risk of developing cardiogenic shock (i.e. age > 70 years, heart rate > 110 beats/min, systolic blood pressure < 120 mmHg), the observed shock or death rate was significantly increased [83]. Therefore, early administration of beta-blockers should be avoided in these patients if the ventricular function is unknown.

Contraindications include heart rate <60 bpm, systolic BP <100 mmHg, moderate or severe associated left ventricular failure, PR interval on the ECG >0.24 s, second- or third-degree heart block, active asthma/reactive airways disease, severe COPD, hypotension, right ventricular infarction, and cardiogenic shock. Beta-blockers should not be administered in patients with symptoms possibly related to coronary vasospasm or cocaine use, as they might favor spasm by leaving alpha-mediated vasoconstriction unopposed by beta-mediated vasodilation.

suggests that aspirin administration (up to 2 years) is associated with a highly significant 46% odds reduction in major vascular events [90]. There was no difference between higher-dose

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Clopidogrel (300–600 mg loading and 75 mg/day maintenance dose) is an inactive prodrug that requires oxidation by the hepatic cytochrome P450 (CYP) system to generate an active metabolite. Clopidogrel is a selective and irreversible inhibitor of platelet P2Y12 receptors and thus inhibits ADP-induced platelet aggregation [92, 93]. Dual antiplatelet therapy (DAPT) comprising aspirin and clopidogrel has been shown to reduce recurrent ischemic events in the NSTE-ACS setting compared with aspirin alone [94, 95]. However, up to 10% of patients treated with the combination of aspirin and clopidogrel will have a recurrent ischemic event in the first year after an ACS, with a rate of stent thrombosis of up to 2% [96]. There is substantial inter individual variability in the antiplatelet response to this drug and an increased risk of ischemic and bleeding events in Clopidogrel hypo- and hyper-responders, respectively [97–100]. There is evidence that key gene polymorphisms are involved in both the variability of active

Prasugrel (60 mg loading and 10 mg/day maintenance dose) is a prodrug that irreversibly blocks platelet P2Y12 receptors with a faster onset and a more profound inhibitory effect than clopidogrel. In the TRITON-TIMI 38, Prasugrel reduced recurrent CV event in ACS patients scheduled for PCI in comparison to clopidogrel, significantly driven by reduction in MI [105]. There were more severe bleeding complications with prasugrel, due to an increase in spontaneous and fatal bleeds [106]. Based on the marked reduction in definite or probable stent thrombosis observed in the TRITON-TIMI 38 prasugrel should be considered in patients with stent thrombosis despite compliance with clopidogrel therapy [100, 107]. Prasugrel is contraindicated in patients with prior stroke/transient ischemic attack due to evidence of net harm in this group in TRITON-TIMI 38. In addition, the study showed no apparent benefit in

Ticagrelor is an oral, reversibly binding P2Y12 inhibitor with a plasma half-life of 6–12 h.

Like prasugrel, ticagrelor has a more rapid and consistent onset of action compared with Clopidogrel, as well as a faster offset of action with more rapid recovery of platelet function [108]. In the PLATO trial, the primary composite efficacy endpoint (death from CV causes, MI or stroke) was significantly reduced with ticagrelor compared with similar reductions for CV and all-cause mortality [109, 110]. There was increased risk of non-CABG-related major bleeds with ticagrelor compared with Clopidogrel but no difference in life-threatening or fatal bleeds [110].

(300–325 mg/day) and lower dose (75–100 mg/day) aspirin [91].

metabolite generation and clinical efficacy of Clopidogrel [101–104].

patients >75 years of age or with low bodyweight (<60 kg) [105].

*7.4.2. P2Y12 inhibitors*

*7.4.2.1. Clopidogrel*

*7.4.2.2. Prasugrel*

*7.4.2.3. Ticagrelor*

## **7.3. Initial antiplatelet/anticoagulant**

#### *7.3.1. Bleeding risk assessment*

The CRUSADE bleeding risk score considered baseline patient characteristics (i.e. female gender, history of diabetes, history of peripheral vascular disease or stroke), admission clinical variables (i.e. heart rate, systolic blood pressure, signs of heart failure) and admission laboratory values (i.e. hematocrit, calculated creatinine clearance) to estimate the patient's likelihood of an in-hospital major bleeding event [84].

The Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) bleeding risk score was derived from a pooled cohort recruited in the ACUITY and HORIZONS-AMI trials [85]. Six independent baseline predictors were identified including: female gender, advanced age, elevated serum creatinine, white blood cell count, anemia and presentation as NSTEMI or STEMI and one treatment-related variable [use of unfractionated heparin and a glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor rather than bivalirudin alone]. This risk score identified patients at increased risk for non-CABG-related major bleeds at 30 days and subsequent 1-year mortality. However, it has not been validated in an independent cohort.

Changes in interventional practice, such as increasing use of radial access, reduction in the dose of UFH, use of bivalirudin, diminished use of GPIIb/IIIa inhibitors and administration of more effective inhibitors of the platelet adenosine diphosphate (ADP) receptor P2Y12 (P2Y12 inhibitors), may all modify the predictive value of risk scores. Ischemic and bleeding risks need to be weighed in the individual patient, although many of the predictors of ischemic events are also associated with bleeding complications [84, 85]. Overall, CRUSADE and ACUITY scores have reasonable predictive value for major bleeding in ACS patients undergoing coronary angiography, with CRUSADE found to be the most discriminatory [86].

#### **7.4. Platelet inhibition**

#### 7.4.1. *Aspirin*

Aspirin (chewed) is indicated immediately for all patients suspected of having an acute coronary syndrome unless contraindicated or already taken [1]. Aspirin should be continued at a daily maintenance dose thereafter [1]. Aspirin, an irreversible COX-1 inhibitor, suppresses thromboxane A2 production preventing platelet aggregation, and reduces the incidence of death and nonfatal MI in patients with unstable angina or acute MI [87, 88]. Aspirin has been shown to achieve a 30–51% reduction in future coronary events [89]. A meta-analysis suggests that aspirin administration (up to 2 years) is associated with a highly significant 46% odds reduction in major vascular events [90]. There was no difference between higher-dose (300–325 mg/day) and lower dose (75–100 mg/day) aspirin [91].

## *7.4.2. P2Y12 inhibitors*

#### *7.4.2.1. Clopidogrel*

Contraindications include heart rate <60 bpm, systolic BP <100 mmHg, moderate or severe associated left ventricular failure, PR interval on the ECG >0.24 s, second- or third-degree heart block, active asthma/reactive airways disease, severe COPD, hypotension, right ventricular infarction, and cardiogenic shock. Beta-blockers should not be administered in patients with symptoms possibly related to coronary vasospasm or cocaine use, as they might favor spasm by leaving alpha-mediated vasoconstriction unopposed by beta-mediated vasodilation.

The CRUSADE bleeding risk score considered baseline patient characteristics (i.e. female gender, history of diabetes, history of peripheral vascular disease or stroke), admission clinical variables (i.e. heart rate, systolic blood pressure, signs of heart failure) and admission laboratory values (i.e. hematocrit, calculated creatinine clearance) to estimate the patient's likeli-

The Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) bleeding risk score was derived from a pooled cohort recruited in the ACUITY and HORIZONS-AMI trials [85]. Six independent baseline predictors were identified including: female gender, advanced age, elevated serum creatinine, white blood cell count, anemia and presentation as NSTEMI or STEMI and one treatment-related variable [use of unfractionated heparin and a glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitor rather than bivalirudin alone]. This risk score identified patients at increased risk for non-CABG-related major bleeds at 30 days and subsequent 1-year mor-

Changes in interventional practice, such as increasing use of radial access, reduction in the dose of UFH, use of bivalirudin, diminished use of GPIIb/IIIa inhibitors and administration of more effective inhibitors of the platelet adenosine diphosphate (ADP) receptor P2Y12 (P2Y12 inhibitors), may all modify the predictive value of risk scores. Ischemic and bleeding risks need to be weighed in the individual patient, although many of the predictors of ischemic events are also associated with bleeding complications [84, 85]. Overall, CRUSADE and ACUITY scores have reasonable predictive value for major bleeding in ACS patients undergoing coronary angiography, with CRUSADE found to be the most

Aspirin (chewed) is indicated immediately for all patients suspected of having an acute coronary syndrome unless contraindicated or already taken [1]. Aspirin should be continued at a daily maintenance dose thereafter [1]. Aspirin, an irreversible COX-1 inhibitor, suppresses thromboxane A2 production preventing platelet aggregation, and reduces the incidence of death and nonfatal MI in patients with unstable angina or acute MI [87, 88]. Aspirin has been shown to achieve a 30–51% reduction in future coronary events [89]. A meta-analysis

**7.3. Initial antiplatelet/anticoagulant**

hood of an in-hospital major bleeding event [84].

tality. However, it has not been validated in an independent cohort.

*7.3.1. Bleeding risk assessment*

72 Myocardial Infarction

discriminatory [86].

7.4.1. *Aspirin*

**7.4. Platelet inhibition**

Clopidogrel (300–600 mg loading and 75 mg/day maintenance dose) is an inactive prodrug that requires oxidation by the hepatic cytochrome P450 (CYP) system to generate an active metabolite. Clopidogrel is a selective and irreversible inhibitor of platelet P2Y12 receptors and thus inhibits ADP-induced platelet aggregation [92, 93]. Dual antiplatelet therapy (DAPT) comprising aspirin and clopidogrel has been shown to reduce recurrent ischemic events in the NSTE-ACS setting compared with aspirin alone [94, 95]. However, up to 10% of patients treated with the combination of aspirin and clopidogrel will have a recurrent ischemic event in the first year after an ACS, with a rate of stent thrombosis of up to 2% [96]. There is substantial inter individual variability in the antiplatelet response to this drug and an increased risk of ischemic and bleeding events in Clopidogrel hypo- and hyper-responders, respectively [97–100]. There is evidence that key gene polymorphisms are involved in both the variability of active metabolite generation and clinical efficacy of Clopidogrel [101–104].

## *7.4.2.2. Prasugrel*

Prasugrel (60 mg loading and 10 mg/day maintenance dose) is a prodrug that irreversibly blocks platelet P2Y12 receptors with a faster onset and a more profound inhibitory effect than clopidogrel. In the TRITON-TIMI 38, Prasugrel reduced recurrent CV event in ACS patients scheduled for PCI in comparison to clopidogrel, significantly driven by reduction in MI [105]. There were more severe bleeding complications with prasugrel, due to an increase in spontaneous and fatal bleeds [106]. Based on the marked reduction in definite or probable stent thrombosis observed in the TRITON-TIMI 38 prasugrel should be considered in patients with stent thrombosis despite compliance with clopidogrel therapy [100, 107]. Prasugrel is contraindicated in patients with prior stroke/transient ischemic attack due to evidence of net harm in this group in TRITON-TIMI 38. In addition, the study showed no apparent benefit in patients >75 years of age or with low bodyweight (<60 kg) [105].

#### *7.4.2.3. Ticagrelor*

Ticagrelor is an oral, reversibly binding P2Y12 inhibitor with a plasma half-life of 6–12 h.

Like prasugrel, ticagrelor has a more rapid and consistent onset of action compared with Clopidogrel, as well as a faster offset of action with more rapid recovery of platelet function [108].

In the PLATO trial, the primary composite efficacy endpoint (death from CV causes, MI or stroke) was significantly reduced with ticagrelor compared with similar reductions for CV and all-cause mortality [109, 110]. There was increased risk of non-CABG-related major bleeds with ticagrelor compared with Clopidogrel but no difference in life-threatening or fatal bleeds [110]. There was a reduction in definite stent thrombosis with ticagrelor in the NSTE-ACS subgroup. In addition to increased rates of minor or non-CABG-related major bleeding events with ticagrelor, adverse effects included dyspnea (without bronchospasm), increased frequency of asymptomatic ventricular pauses and increases in uric acid [109, 111, 112].

**9. Ischemia-guided strategy versus early invasive strategies**

acute or chronic (CKD 4 or higher) renal failure or multi-organ failure [1, 123, 124].

episodes, subsequent rehospitalization and revascularization [125–127].

• Rise and fall in cardiac biomarkers (troponin T or I) consistent with MI

• Signs or symptoms of heart failure, or new or worsening mitral regurgitation

Invasive coronary angiography allows to confirm the diagnosis of ACS related to obstructive epicardial CAD, to guide antithrombotic treatment, identify the culprit lesions and assess the suitability of coronary anatomy for PCI or CABG. Routine invasive strategy in NSTEMI has been shown to improve clinical outcomes and lower risk of death, reduce recurrent ischemic

Urgent and immediate angiography is indicated if patients do not stabilize with intensive medical treatment [1]. Guidelines recommend that an invasive approach is appropriate if any

• Recurrent angina or ischemia at rest or with low-level activities despite intensive medical

Once initial management is instigated, the decision should be made as to whether the patient requires treatment using an invasive or noninvasive approach. The decision to pursue an invasive approach or medical management is made on an individual basis [122]. Invasive strategy carries risks but the benefit includes diagnostic accuracy, risk stratification and revascularization. The timing for coronary angiography and the selection of the revascularization modality depend on numerous factors, including clinical presentation, comorbidities, risk stratification, presence of high-risk features specific for a revascularization modality, frailty, cognitive status, estimated life expectancy and functional and anatomic severity as well as pattern of CAD. Guidelines recommend that high-risk patients routinely undergo early (12–24 h) coronary angiography and angiographically directed revascularization if possible unless patients have serious comorbidities, including cancer or end-stage liver disease, or clinically obvious contraindications, including

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**9.1. Rationale and timing for early invasive strategy**

**9.2. Routine invasive coronary angiography**

of the following high-risk features are present [1, 15]:

• New or dynamic ST-T wave changes

• High-risk score (i.e., TIMI, GRACE) • Mild to moderate renal dysfunction

• Hemodynamic instability

• PCI within 6 months

• Prior CABG

• Life-threatening arrhythmia

therapy

All patients should be given dual antiplatelet therapy with a P2Y12 receptor inhibitor in addition to aspirin. If the patient is intolerant of aspirin or it is otherwise contraindicated, a P2Y12 receptor inhibitor can be given instead of aspirin, but two different P2Y12 receptor inhibitors should not be given together. P2Y12 receptor inhibitors can reduce mortality and morbidity, but they are associated with an increased risk of bleeding [113, 114]. Ticagrelor and prasugrel are newer P2Y12 agents, which trials have shown to have a faster onset of action and greater efficacy compared with Clopidogrel [1, 115]. However, the risk of bleeding is also greater with these two P2Y12 agents compared with Clopidogrel [116, 117].

Clinicians need to tailor therapy to strike a balance between a newer agent that may have a faster onset of action and greater antiplatelet effect, but could potentiate bleeding (especially in those with prior TIA or stroke). Regardless of which P2Y12 receptor inhibitor is chosen, a loading dose should be given as soon as possible in most patients and then a maintenance dose continued for a minimum of 12 months [118].

#### **7.5. Anticoagulation**

Anticoagulation therapy (subcutaneous low molecular weight heparin, intravenous unfractionated heparin, or the alternative agents fondaparinux or bivalirudin) should be started on earliest recognition of NSTEMI. The anticoagulant is used in conjunction with antiplatelet therapy already started (i.e., aspirin and a P2Y12 receptor inhibitor). If fondaparinux is used during angiography/PCI, guidelines recommend that UFH be used in addition [1].

Anticoagulation should not be given if there are contraindications like major bleeding, history of adverse drug reaction or heparin-induced thrombocytopenia.

The antiplatelet and anticoagulation regimens should be started before the diagnostic angiogram. Triple antiplatelet therapy, in which an intravenous GP IIb/IIIa inhibitor is added to a P2Y12 receptor inhibitor, aspirin, and anticoagulation, can be considered for high-risk patients; however, it should be avoided in patients at high risk of bleeding [1]. Although guidelines recommend the use of GP IIb/IIIa inhibitors in NSTEMI, the level of evidence for their routine use is weak at best, particularly as results from randomized trials are conflicting [119, 120].
