CAT 2

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SECTION 1 Cardiovascular Medicine

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CHAPTER 128 Acute Coronary Syndromes

Michael McDaniel, MD, FSCAI

Key Clinical Questions

What is the optimal care and management of patients with ST-segment elevation myocardial infarction?

What is the optimal care and management of patients with non-ST segment elevation acute coronary syndrome?

INTRODUCTION

The term acute coronary syndrome (ACS) refers to the spectrum clinical presentations related to acute myocardial ischemia or infarction due to the abrupt reduction in coronary blood flow. ACS is divided into ST-segment elevation myocardial infarctions (STEMIs) and non-ST segment elevation acute coronary syndromes (NSTE-ACSs). The NSTE-ACS is further subdivided on the basis of elevated cardiac biomarkers of myocardial necrosis. Patients with elevated cardiac biomarkers are defined as non-ST segment elevation myocardial infarction (NSTEMI) and those without elevated biomarkers are termed unstable angina (UA).

This chapter will focus on the diagnosis, risk stratification, and treatment of patients with ACS based on the American College of Cardiology Foundation and American Heart Association (ACCF/AHA) practice guidelines for STEMI and NSTE-ACS. All guideline recommendations will be cited in this chapter and referenced according the American

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College of Cardiology Foundation/American Heart Association classification scheme (Table 128-1).

TABLE 128-1 ACCF/AHA Classification of Recommendations and Level of Evidence

Class I Class IIa Class IIb Class III Benefit >>> Risk Procedure/Treatment SHOULD be performed/administered

Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment

Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED

Risk ≥ Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL

Level A: Recommendation based on evidence from multiple randomized trials or meta-analyses Level B: Recommendation based on evidence from a single randomized trial or non- randomized studies Level C: Recommendation based on expert opinion, case studies, or standard of care

From O’Gara PT, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol.2013;61(4):485-510.

EPIDEMIOLOGY & PATHOPHYSIOLOGY

ACS is common, with over 780,000 patients experiencing an ACS event every year in the United States. Of these events, approximately 70% are classified as NSTE-ACS. ACS is related to an acute imbalance of myocardial oxygen consumption and demand, usually related to a sudden coronary artery obstruction. Autopsy studies suggest that most ACS events are related to acute coronary thrombosis, with acute plaque rupture being the most common etiology. The atherosclerosis at sites of plaque rupture is characterized by large lipid-laden necrotic cores overlying a disrupted thin fibrous cap. The second most common cause of acute coronary thrombosis is plaque erosion, characterized by thrombus formation at an area of denuded endothelium. These plaques are characterized by smaller plaques with less lipid necrotic core and thicker fibrous caps compared to plaque rupture sites. Plaque erosion is actually the most common etiology of acute coronary thrombosis in younger female patients, especially those who smoke tobacco. More rare causes of coronary thrombosis are due to the calcified nodule which is not well characterized and is mostly seen in the elderly, and cardioembolic etiologies which are usually noted in distal coronary locations. Nonthrombotic sudden progressions in coronary arteries may be related to acute intraplaque hemorrhage without thrombosis. Rarely, acute coronary insufficiency may be caused by vasospasm, coronary arteritis, or spontaneous dissection.

HISTORY AND PHYSICAL

The most common clinical presentation of ACS is new onset pressure-like chest pain that occurs at rest (>10-20 minutes in duration) or with minimal activity. The pain is often

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retrosternal and can radiate to the arm (likelihood ratio [LR] 2.7), neck, or jaw and may be associated with diaphoresis (LR 2.0), dyspnea, or nausea (LR 1.9). However, chest pain can be absent in one-third of patients. Less common presentations of ACS include syncope, abdominal pain, hypotension, pulmonary edema, or unexplained fatigue. While older women and patients with diabetes most commonly present with typical symptoms of ACS, atypical ACS presentations are most common in these patients. Symptoms that are not characteristic of myocardial ischemia included pleuritic pain (LR 0.2), sharp or stabbing pain localized to a single location (LR 0.3), pain reproduced by palpitation (LR 0.2-0.4), or brief episodes lasting only seconds. Risk factors for ACS include older age, male sex, family history of coronary artery disease (CAD), peripheral arterial disease, diabetes mellitus, renal insufficiency, and prior CAD. The differential diagnosis for ACS is listed in Table 128-2.

TABLE 128-2 Differential Diagnosis for NSTE-ACS

Nonischemic Cardiovascular • Aortic dissection • Expanding aortic aneurysm • Myocarditis • Pericarditis • Hypertrophic cardiomyopathy • Pulmonary embolism Pulmonary • Pneumonia • Pleuritis • Pulmonary hypertension • COPD • Pneumothorax Gastrointestinal • Gastroesophageal reflux • Esophageal spasm • Esophagitis • Esophageal hypersensitivity • Peptic ulcer • Pancreatitis • Biliary obstruction Musculoskeletal • Cervical disk radiculopathy • Costochondritis • Rheumatic disease • Trauma Other etiologies • Sickle cell crisis • Herpes zoster

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• Depression and anxiety • Drug intoxication • Pheochromocytoma

Reprinted from Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-228 with permission from Elsevier, Inc.

The physical examination may be completely normal in many patients with ACS. Signs and symptoms of new congestive heart failure, mitral regurgitation, and/or shock suggest higher risk and usually require more emergent triage, treatment, and often invasive therapies. Signs of low cardiac output may be suggested by tachycardia, cool extremities, diaphoresis, confusion, and/or reduced urine output. Signs of congestive heart failure include elevated jugular venous distension, pulmonary edema, audible S3, and/or lower extremity edema.

ELECTROCARDIOGRAM

To rapidly identify STEMI, an electrocardiogram (ECG) should be performed within 10 minutes of arrival to the emergency department (ED) in all patients with signs and symptoms of ACS (Class I, Level of Evidence [LOE] C). In addition, Emergency Medical Service (EMS) personnel should perform a 12-lead ECG on site in all patients with suspected ACS and transport patients with STEMI to percutaneous coronary intervention (PCI)-capable facilities, where available.

STEMI is defined on ECG by new ST-elevation in at least two contiguous leads ≥2 mm in leads V2-V3 or ≥1 mm in the other chest leads or limb leads. Abnormalities alone on the EKG are insufficient to make a diagnosis of STEMI and the ECG must be interpreted in the appropriate clinical context. While new left bundle branch block (LBBB) was once considered as an STEMI equivalent, guidelines now recommend the LBBB in isolation should not be considered diagnostic of acute myocardial infarction (AMI) and specific ECG criteria have been proposed to diagnose STEMI in LBBB (Table 128-3). In addition, ST depressions in V1-V4 may indicate posterior injury (Figure 128-1) and isolated ST- elevation in aVR and/or V1 with diffuse ST depression may suggest acute left main or proximal left anterior descending artery occlusion (Figure 128-2). Rarely, hyperacute T- waves can be seen early in patients with STEMI. When the initial ECG is nondiagnostic and the patient remains symptomatic, serial ECGs should be performed at 15 to 30 minute intervals during the first hour or if symptoms recur (Class I, LOE C).

TABLE 128-3 ECG Criteria for Diagnosis of STEMI in the Setting of Left Bundle Branch Block (Sgarbossa Criteria)

Criterion Odds Ratio (95% CI) Score ST-elevation ≥1 mm and concordant with QRS complex

25.2 (11.6-54.7) 5

ST-segment depression >1 mm in leads V1, V2, or V3

6.0 (1.9-19.3) 3

ST-elevation >5 mm and discordant with QRS complex

4.3 (1.8-10.6) 2

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A score >3 had a 98% specificity for acute myocardial infarction, but a score of 0 does not rule out STEMI.

From O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST- elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 29;61(4):e78-140. Reprinted with permission from Elsevier, Inc.

Figure 128-1 EKG with and ST-depression in V1-V3 suggestive of acute posterior injury. (Reproduced, by permission, from Knoop KE, et al eds. The Atlas of Emergency Medicine, 3rd ed. New York, NY: McGraw-Hill; 2010. ECG contributor: Ian D. Jones, MD.)

Figure 128-2 ST-elevation in aVR with diffuse ST depression consistent with acute left main or very proximal left anterior descending artery occlusion.

The 12-lead ECG may suggest a diagnosis of NSTE-ACS, but is not required to make the diagnosis. Horizontal or downsloping dynamic ST-segment depression is highly suggestive of NSTE-ACS. In addition, significant deep precordial T-wave inversion (Wellen’s sign) may suggest critical left anterior descending stenosis (Figure 128-3). More nonspecific ST-T changes are less diagnostic. Significant Q-waves can suggest a prior myocardial infarction (MI), but do not suggest ACS.

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Figure 128-3 Deep T-wave inversion in the precordial leads suggestive of ischemia in the left anterior descending coronary artery (Wellen’s sign).

ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION (STEMI)

MANAGEMENT OF STEMI AT PCI-CAPABLE HOSPITALS

All hospitals should develop coordinated regional approaches to STEMI care and participation in programs such as Mission:Lifeline (American Heart Association’s Mission: Lifeline: http://www.heart.org) and the D2B Alliance is recommended (Class I, LOE B). These initiatives promote prehospital ECG to diagnose STEMI, EMS and ED activation of cardiac catheterization labs (“cath labs”), single calls to central paging operator to activate the cath team, cath lab staff arrival within 20 to 30 minutes of notification, and timely data feedback to all members of the STEMI team.

Once the diagnosis of STEMI is made, the most important therapy for patients is emergent revascularization within 90 minutes of first medical contact (FMC) (Class I, LOE A). As such, it is preferred for patients to bypass the ED and present directly via EMS to the cath lab when possible to optimize reperfusion times (Figure 128-4). Most patients arriving by EMS with ACS will receive aspirin 325 mg by EMS personnel (Class I, LOE A). Patients should also receive an unfractionated heparin (UFH) bolus (50-70 units/kg, max 5000 units) as soon as possible upon hospital arrival (Class I, LOE C). In addition, all patients presenting with STEMI should receive a loading dose of an oral antiplatelet P2Y12 antagonist as early as possible (Class I, LOE B). Presently, there are three options of the oral antiplatelet P2Y12 antagonists: clopidogrel 600 mg, prasugrel 60 mg, and ticagrelor 180 mg. Choosing between these agents will be discussed later in the Dual Antiplatelet Therapy Section of Late Hospital & Hospital Discharge part of the chapter.

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Figure 128-4 Algorithm for evaluation and management of acute coronary syndrome for PCI-capable hospitals. ACS, acute coronary syndromes; ASA, aspirin; CCU, coronary care unit; CP, chest pain; ECG, electrocardiogram; Non-STE ACS, Non-ST segment elevation acute coronary syndrome; NTG, nitroglycerin; PCI, percutaneous coronary intervention; PO, Per Os; SL, sublingual; STEMI, ST-segment elevation myocardial infarction.

There is little benefit to intravenous (IV) glycoprotein IIb/IIIa inhibitors (GPIs) prior to angiography in STEMI (Class IIb, B). However, GPIs are indicated in many patients during and after PCI for STEMI as it blocks the final common pathway of platelet activation. While a comprehensive review of the GPI trials is beyond the scope of this chapter, a few general principals regarding GPIs deserve mention. GPIs provide very rapid inhibition of platelets, much greater and faster than oral P2Y12 inhibitors. In addition, pooled studies suggest that GPIs reduce recurrent 30-day unplanned revascularization and mortality in STEMI. In a meta-analysis of 7414 patients from multiple randomized trials, patients undergoing PCI for STEMI receiving GPIs have about a 25% relative decrease in mortality compared to no GPI. However, GPIs are clearly associated with about a 50% relative increase in bleeding

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complications, especially with femoral access. This bleeding is attenuated but not eliminated by radial access. Currently, there are three GPI agents available for clinical use. There are two small molecule agents, eptifibatide and tirofiban, and one large molecule agent abciximab. Randomized trials, registries, and meta-analyses suggest that the large and small molecule GPI agents have similar efficacy and safety in patients undergoing primary PCI. As such, the choice of GPI may be driven more by cost considerations.

Bivalirudin is a direct thrombin inhibitor that has been studied extensively in primary PCI in STEMI, but its use is controversial given conflicting recent studies. In both the 3602 patient Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS AMI) and the 2218 patient European Ambulance Acute Coronory Syndrome angiography study (EUROMAX) trials, there were significantly less bleeding complications in patients randomized to bivalirudin compared to the combination of UFH and planned or provisional GPI. However, there was also significant more acute stent thrombosis, and the bleeding reduction was attenuated in patients with radial access. More recently, the benefits of bivalirudin compared to UFH alone have been questioned. In the How Effective Are Antithrombotic Therapies in Primary PCI (HEAT PPCI) trial, 1812 patients with STEMI were randomized to bivalirudin or UFH, both with provisional use of GPI. In this trial, there was no reduction of bleeding with the use of bivalirudin and actually higher major cardiac events with bivalirudin. It should be noted however that the use of provisional GPI was low and similar in both groups and most patients underwent PCI using the radial approach. Given the significantly higher cost compared to UFH, it is controversial if bivalirudin provides value compared to UFH, and further studies are warranted to best define the optimal role of bivalirudin in STEMI.

The radial access is increasingly utilized in STEMI as this strategy decreases access- site complications compared to PCI via femoral access (Class IIa, LOE A). In the 1001 patient Radial versus Femoral Randomized Investigation in ST Elevation Acute Coronary Syndrome trial, patients randomized to radial access had lower bleeding at 30 days (7.8% vs 12.2%, number needed to treat [NNT]23, P = 0.026) and cardiac mortality (5.2% vs 9.2%, NNT25, P = 0.02) compared with patients randomized to femoral access. Similar findings were noted in a meta-analysis of 5055 patients from 11 randomized trials in STEMI.

MANAGEMENT OF STEMI AT NON-PCI-CAPABLE HOSPITALS

Not all patients with STEMI present to hospitals that can perform primary PCI. These patients should be transferred to a PCI-capable hospital for primary PCI if this transport can occur rapidly and achieve revascularization at the receiving hospital with FMC-to- device time less than120 minutes (Class I, LOE B). If this time goal cannot be met, fibrinolytic therapy is recommended in the absence of contraindications within 30 minutes of hospital arrival (Class I, LOE B). Fibrin-specific agents (Tenecteplase, Reteplase, and Alteplase) are preferred over non-fibrin-specific agents (Streptokinase). Absolute and relative contraindications to fibrinolytic therapy are listed in Table 128-4. In addition, patients presenting with cardiogenic shock, high bleeding risk, or presentations >3 to 4 hours after symptom onset should usually be transported to a PCI-capable hospital regardless of transport times.

TABLE 128-4 Contraindications to Fibrinolysis in STEMI

Absolute Contraindications • Prior intracranial hemorrhage

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• Structural cerebral vascular lesions • Malignant intracranial neoplasm • Ischemic stroke within 3 mo • Suspected aortic dissection • Active bleeding • Significant closed-head or facial trauma within 3 mo • Intracranial or intraspinal surgery within 2 mo • Severe uncontrolled hypertensions unresponsive to therapy Relative Contraindications • Significant hypertension (SBP >180 mm Hg or DBP >110 mm Hg) • History of ischemic stroke >3 mo • Dementia • Prolonged CPR >10 min • Major surgery within 3 wk • Recent internal bleeding within 2-4 wk • Noncompressible vascular punctures • Pregnancy • Active peptic ulcer • Oral anticoagulant therapy

All patients who receive fibrinolysis should also receive aspirin 325 mg PO loading dose, clopidogrel 300 mg PO loading dose, and unfractionated heparin bolus and infusion. In addition, all patients should be transferred emergently to a PCI-capable hospital for urgent/emergent angiography as part of either a rescue PCI strategy (for failed lysis) or a pharmocoinvasive strategy as both strategies have been shown to improve outcomes compared to conservative management strategies.

COMATOSE PATIENTS WITH OUT-OF-HOSPITAL CARDIAC ARREST

Comatose patients with out-of-hospital cardiac arrest (OHCA) due to ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) with return of spontaneous circulation (ROSC) deserve special mention. These patients have about a 10-fold increase in mortality compared to STEMI patients without cardiac arrest. Survival is optimized when CPR and defibrillation are initiated early. Importantly, the neurologic exam should not be used in the acute setting to predict future neurologic recovery or survival. While patients with longer pulseless times, unwitnessed arrests, and longer CPR durations have worse neurologic outcomes, there are no absolute predictors in the acute setting of neurologic recovery with intervention. As such, the neurologic status should not solely be used to guide decisions about invasive procedures in the acute setting.

Immediate angiography and PCI should be strongly considered for all comatose patients with OHCA and ROSC with STEMI on initial ECG (Class I, LOE B). In addition, targeted temperature management (TTM) should be started as soon as possible to target 32°C to 34°C for 12 to 24 hours (Class I, LOE B). Two randomized trials have reported improved neurologic survival when TTM was initiated before or at the time of PCI, and the combination of early angiography/intervention and TTM is associated with the highest survival and neurologic recovery. More recently, other randomized clinical trials of TTM in

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postresuscitated patients have found equally impressive survival rates, whether cooled to 33°C versus 36°C or whether initiated in the field or after arrival at the hospital. Several methods for hypothermia are available, but there are insufficient data to recommend one technique over another and local expertise should guide decisions between external cooling pads, intravascular cooling, cooling blankets, and ice packs. Of note, iced saline should rarely be used as the volume may precipitate pulmonary edema in patients at risk for heart failure and this can lead to more rapid fluctuations in body temperature.

While there is not a consensus to the optimal management of patients with OHCA due to VF/VT with ROSC without ST-elevations on ECG, most of the studies also support early angiography, PCI, and TTM for these patients as up to 25% to 30% of these patients will have culprit lesions at angiography despite a normal ECG. However, given the greater heterogeneity of these patients, consultation should be undertaken with interventional cardiology prior to cath lab activation for these patients.

PRACTICE POINT

STEMI Rapid ECG with interpretation is recommended prehospital by EMS or within 10 minutes of arrival to the hospital to rapidly identify patients with STEMI and optimize reperfusion times. When the initial ECG is nondiagnostic and the patient remains symptomatic, serial ECGs should be performed at 15- to 30-minute intervals during the first hour or if symptoms recur. Left Bundle Branch Block in isolation should not be considered diagnostic of acute myocardial infarction and specific ECG criteria have been proposed to diagnose STEMI in LBBB (Table 128-3). All patients with STEMI should receive an aspirin loading dose (325 mg), unfractionated heparin bolus (50-70 units/kg, max 5000 units), and a P2Y12 inhibitor loading dose prior to or at the time of angiography. Primary PCI is recommended within 90 minutes of first medical contact for PCI- capable hospitals. Transfer for primary PCI from a non-PCI-capable hospital is recommended when the first medical contract to device time (balloon or aspiration catheter) can be accomplished within 120 minutes. When this is not possible, fibrinolysis is preferred within 30 minutes of hospital arrival. The optimal use of glycoprotein IIb/IIIa inhibitors and Bivalirudin in STEMI remains controversial. When GPIs are used, they should usually be deferred until angiography is performed. Most comatose patients with out-of-hospital cardiac arrest due to VT/VF and return of spontaneous circulation should undergo emergent angiography and targeted temperature management.

NON-ST SEGMENT ELEVATION ACUTE CORONARY SYNDROMES (NSTE-ACS) MORPHINE, OXYGEN, NITROGLYCERIN, AND ASPIRIN

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“MONA” (Morphine, Oxygen, Nitroglycerin, and Aspirin) has been part of the classic teaching for patients with ACS for decades. However, aside from aspirin, there are now reasons to caution the routine use of these other agents in ACS.

Morphine should probably be avoided in most patients with active angina as it can mask ongoing ischemia or infarction in patients who may benefit from emergent revascularization, and its use has been downgraded in recent guidelines (Class IIb, LOE B) based on observational studies suggesting an association with adverse events and morphine use in ACS. While this may be related to the fact that sicker patients get morphine, morphine may mask the pain of ongoing infarction resulting in delays in revascularization and larger infarctions. Furthermore, morphine may impair the absorption of the oral antiplatelet agents. For most patients with active angina despite IV nitroglycerin, urgent coronary angiography should be considered instead of morphine.

Supplemental oxygen therapy is recommended only in patients with ACS and arterial oxygen saturation less than 90% or in respiratory distress (Class I, LOE C). The benefits of routine oxygen use without hypoxia have never been demonstrated, and some studies suggest that oxygen therapy may actually increase vascular resistance, reduce coronary flow, and result in larger infarctions. Furthermore, in a pooled Cochrane analysis of 430 patients from four randomized trials demonstrated a twofold higher risk of death in patients with AMI treated with oxygen. Taken together, routine oxygen therapy is probably not necessary in most patients with ACS unless hypoxia is present.

Nitrates are endothelium-independent vasodilators that relieve angina by decreasing cardiac preload and reducing ventricular wall tension. Sublingual (SL) nitroglycerin is recommended for patients with active angina (Class I, LOE C). If the angina continues despite 3 SL nitroglycerin, IV nitroglycerin should be given and titrated until chest pain free or limited by side effects such as hypotension or headache (Class I, LOE B). While nitroglycerin is effective at reducing the symptoms of angina, randomized trials have never demonstrated improved morbidity or mortality outcomes with nitrates. In addition, nitroglycerin should be avoided in patients with hypotension, right ventricular infarctions, and recent phosphodiesterase inhibitor-5 (sildenafil, vardenafil, or tadalafil) use due to risk of significant hypotension (Class III, LOE B).

All patients with ACS should receive nonenteric-coated ASA of 325 mg as soon as possible followed by 81 mg daily maintenance dose (Class I, LOE A). Aspirin is a mainstay of ACS therapy, results in thromboxane A2 inhibition via irreversible COX-inhibition, and results in approximately 30% to 45% relative reductions in death and recurrent myocardial infarction across a large spectrum of ACS. Enteric-coated aspirin should be avoided in the early setting of ACS due to delayed absorption.

SERIAL TROPONIN ANALYSIS

Increasingly, a troponin-only biomarker strategy (without ordering creatine kinase [CK] and creatine kinase myocardial enzyme [CK-MB] fraction) is used for the evaluation of AMI in NSTE-ACS. Although damaged cardiac myocytes release several biomarkers, troponins are preferred based on their superior sensitivity and specificity. Cardiac troponin will rise within 2 to 4 hours of symptom onset and will remain elevated for several days. Shorter intervals of serial troponin measurements (such as 0, 3, and 6 hours) more rapidly diagnose and/or rule out AMI (Class I, LOE A). Contemporary sensitive troponin assays now permit earlier serial sampling (in 3 hours vs previous 8 hours) for earlier detection and treatment of AMI. Furthermore, a negative troponin value 6 hours from presentation essentially excludes the diagnosis of AMI (unless recurrent symptoms), leading to earlier diagnostic testing or hospital discharge. It is important for physicians to be aware of the

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troponin assay used in their local hospital, as troponin measures >6 hours from onset may be required with less sensitive older assays. In addition, testing at longer intervals is required (up to 24 hours) if information about infarct size is required.

There is very little value to using other cardiac biomarkers in addition to troponin, as they are both less sensitive and less specific. Furthermore, moderate-sized registries suggest that the addition of CK-MB adds no additional diagnostic information compared to troponin alone. With contemporary troponin assays, CK-MB and myoglobin are not useful in the diagnosis of ACS and the current guidelines recommend against their use (Class III, LOE A). Importantly, elevated troponin values alone are insufficient to make a diagnosis of NSTEMI and should be evaluated in the appropriate clinical context. There are many reasons other than ACS for elevated troponin values (Table 128-5).

TABLE 128-5 Causes of Elevated Cardiac Troponin Values Due to Myocardial Injury

Injury related to primary myocardial ischemia Plaque rupture Intraluminal coronary artery thrombus formation Injury related to supply/demand imbalance Tachy-/bradyarrhythmias Aortic dissection or severe aortic valve disease Hypertrophic cardiomyopathy Cardiogenic, hypovolemic, or septic shock Severe respiratory failure Severe anemia Hypertension Coronary spasm Coronary embolism or vasculitis Coronary endothelial dysfunction Injury not related to myocardial ischemia Cardiac contusion, surgery, ablation, pacing, or defibrillator shocks Rhabdomyolysis with cardiac involvement Myocarditis Cardiotoxic agents, like anthracyclines Multifactorial or indeterminate myocardial injury Heart failure stress (Takotsubo) Pulmonary embolism or pulmonary hypertension Sepsis Renal failure Severe acute neurological diseases, such as stroke or subarachnoid hemorrhage Infiltrative diseases, like amyloidosis or sarcoidosis Strenuous exercise

Modified by permission from Thygesen K. Third Universal Definition of Myocardial Infarction. JACC. 2012;60(16):1586 (table 1). Elsevier Inc.

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EARLY HOSPITAL TRIAGE IN NSTE-ACS

Patients with possible or definite NSTE-ACS represent a broad population with various levels of risk. Of patients presenting to the ED with possible ACS, less than 25% will be diagnosed with UA or AMI. However, on the opposite end, up to 5% of patients with ACS are inappropriately discharged from the hospital without appropriate diagnostic workup. To address these conflicting issues, observation units have been developed in many hospitals and are recommended for low-risk patients with possible ACS. These units have been associated with lower rates of missed acute MI, lower costs, improved patient satisfaction, and decreased admissions for chest pain. While there are several tools used to risk stratify patients for observation units, many hospitals use modifications of the Goldman’s prediction rule as these criteria predict MACE within 72 hours of presentation (Figure 128-4). The modified rule uses four criteria: (1) positive troponin or new acute ST depression ≥1 mm or T-wave inversion in ≥2 contiguous leads in the setting of ACS; (2) ongoing chest pain that is likely ischemic; (3) worsening of previously stable angina, angina after revascularization procedure, or pain that is the same as that associated with a prior MI; (4) rales above both bases or systolic blood pressure <100 (Figure 128-4). The absence of these four factor identifies patients at very low risk of subsequent cardiac events and appropriate for the observation unit (Figure 128-5). In observation units, dual antiplatelet therapy and anticoagulation is usually avoided. Patients undergo serial troponin evaluation, cardiac monitoring, and repeated ECGs. For patients with normal serial troponins and ECGs, stress testing before discharge or within 72 hours of discharge should be considered (Class IIa, LOE B). If patients have recurrent chest pain suggestive of ischemia, increased cardiac biomarkers, or dynamic ECG changes, they are then admitted to the hospital and managed according to inpatient pathways described below.

Figure 128-5 Observation unit low-risk acute coronary syndrome (ACS) protocol.

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ANTIPLATELET THERAPY AT ADMISSION

Patients who are not low risk and/or patients with recurrent symptoms, ECG changes, or positive troponin values are admitted to the hospital for inpatient management (Figure 128-4). In addition to aspirin, dual antiplatelet therapy is recommended as soon as possible after admission to the hospital. There are two oral P2Y12 inhibitor options for upstream management in NSTE-ACS: clopidogrel (600 mg loading dose followed by 75 mg a day) and ticagrelor (180 mg loading dose followed by 90 mg twice a day). Both of these agents are options for both the invasive (Class I, LOE B) and ischemia-guided (Class I, LOE A) strategies. Choice between these agents will be discussed later in the Dual Antiplatelet Therapy Section of Late Hospital & Hospital Discharge part of the chapter.

The early benefit of clopidogrel was first noted in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, where there was a 34% relative reduction in major cardiac events in first 24 hours in patients randomized to clopidogrel and aspirin compared to aspirin alone. Furthermore, in a large meta-analysis of 37,814 patients undergoing PCI from six randomized control trials and nine observational studies showed a significant reduction in major adverse cardiac events (9.8% vs 12.3%, NNT = 40, p < 0.001) and trends toward improve mortality (1.5% vs 2.0%, p = 0.17) with dual antiplatelet therapy pretreatment compared to aspirin alone. The downside to routine upstream clopidogrel is increased bleeding in patients who require coronary artery bypass graft (CABG) surgery. However, CABG is only required in approximately 11% of patients with ACS, and if not emergent, surgery can be delayed 5 days until the antiplatelet effects have reversed.

The oral P2Y12 inhibitor prasugrel is not recommended prior to cardiac catheterization in patients with NSTE-ACS, based on the results of the ACCOST (A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients With Non–ST-Elevation Myocardial Infarction) trial where 4033 patients with non-STE ACS were randomized to upstream or intraprocedural prasugrel. In this trial, there was no reduction in major adverse events but only increased bleeding complications in patients pretreated with prasugrel. It has been suggested that the lack of efficacy in this trial may relate to short time interval from pretreatment to catheterization and the rapid onset of action of the drug in the cardiac cath lab.

Upstream (prior to the cath lab) GPIs are usually not necessary for most patients with ACS in the setting of upstream oral dual antiplatelet therapy. Two randomized studies in NSTE-ACS have noted similar efficacy with a deferred GPI strategy (given at the time of PCI) compared with a routine upstream strategy. In the 10,500 patient Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome trial, there were similar major adverse events (9.3% vs 10%, p = 0.23) with more bleeding in the routine upstream GPI use. Similar findings were noted in the Acute Catheterization and Urgent Intervention Triage strategY Timing Trial.

ANTICOAGULANT THERAPY AT ADMISSION

All patients admitted to the hospital with NSTE-ACS should receive IV anticoagulation prior to cardiac catheterization as well as during PCI. While the optimal anticoagulation strategy in patients with NSTE-ACS is unknown, the most widely used agent is UFH 60 units/kg bolus (maximum 4000 units) followed by an initial infusion of 12 units/kg/h (maximum 1000 units/h) adjusted per activated partial thromboplastin time to maintain therapeutic anticoagulation (Class I, LOE B). UFH does not break down existing thrombus, but does prevent further thrombus formation. While large studies investigating UFH in ACS

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are lacking, meta-analysis suggest about a 33% reduction (relative risk 0.67 [0.44-1.02], NNT = 40) in recurrent ischemia and infarction with the addition of UFH to aspirin. While low molecular weight heparins (LMWHs) offer an alternate option (to UFH) in NSTE-ACS (Class I, LOE A), large randomized trials and meta-analyses suggest essentially similar clinical efficacy and safety compared to unfractionated heparin. However, LMWH must be dose adjusted in patients with low glomerular filtration rates and can significantly delay the sheath removal in the cath lab due to longer durations of action. For these reasons, many interventional cardiologists prefer UFH to LMWH in the cardiac cath lab for patients with NSTE-ACS.

The factor X inhibitor fondaparinux is a synthetic pentasaccharide that indirectly inhibits factor Xa. While lower bleeding complications were noted with fondaprinux compared to LMWH in the OASIS (Organization to Assess Strategies in Ischemic Syndromes)-5 trial, its use should only be considered in a ischemia-guided strategy where invasive procedures are unlikely due to increased rates of catheter thrombosis in patients undergoing PCI. Additional anticoagulation with either unfractionated heparin or bivalirudin is recommended when PCI is warranted with fondaparinux (Class I, LOE B). Furthermore, fondaparinux is contraindicated in patients with GFR < 30 mL/min and the long half-life (17 hours) can delay sheath removal in the cath lab when manual closure is performed. For these reasons, this drug is not ideal for patient with NSTE-ACS in patients with an invasive strategy.

Bivalirudin is an intravenous direct thrombin inhibitor that has been widely studied in patients with NSTE-ACS undergoing an invasive management strategy (Class I, LOE B). Several studies have demonstrated similar efficacy and reduced bleeding complications with bivalirudin compared to routine heparin and GPI use in NSTE-ACS. In the 13,819 patient ACUITY trial, there was a similar composite ischemic endpoint (7.8% vs 7.3%, p = 0.32) but significantly lower major bleeding complications (3.0% vs 5.7%, p < 0.001) with bivalirudin compared to UFH and GPI. Similar findings were noted in ISAR-REACT 4 trial. However, the benefits of bivalirudin over UFH in patients with NSTE-ACS undergoing PCI using the radial access are unknown.

EARLY INVASIVE STRATEGY VERSUS ISCHEMIA-GUIDED STRATEGY

All NSTE-ACS patients with refractory angina, electrical instability (eg, ventricular fibrillation or ventricular tachycardia), and/or cardiogenic shock should undergo immediate angiography within 2 hours of hospital presentation no matter the ECG findings (Class I, LOE A). However, for patients that are hemodynamically and electrically stable without ongoing angina, clinicians must select between an early invasive strategy or an ischemia-guided strategy.

An early invasive strategy is defined as angiography within 72 hours of admission to risk stratify patients based on coronary anatomy. The advantages to an early invasive strategy include rapid evaluation, early revascularizaton, and earlier discharge. An early invasive strategy is indicated for initially stabilized patients with NSTE-ACS without contraindications to angiography and elevated risk of recurrent events (Table 128-6). Multiple studies and meta-analyses suggests that an early invasive strategy is preferred to an ischemia-guided strategy in higher-risk patients with NSTE-ACS as it is associated with lower rates of repeat hospitalization, myocardial infarction, and mortality. In a combined analysis of multiple randomized trials, there was an 11.1% absolute reduction (NNT9) in death and myocardial infarction in the highest risk NSTE-ACS by 5-year follow-up. An early invasive strategy is also associated with less angina and improved quality of life. It should be remembered that these are strategy trials, and not a comparisons of revascularization

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and medical therapy. Patients undergo revascularization with CABG or PCI revascularization in about 70% of patients randomized to an early invasive strategy and in 40% to 50% of patients randomized to an ischemia-guided strategy.

TABLE 128-6 Intermediate or High Risk Non–ST-Elevation Acute Coronary Syndrome (NSTE-ACS) Criteria

Intermediate or High risk NSTE-ACS is defined by one or more of the following: 1. Recurrent angina/ischemia at rest with low-level activities despite intensive medical

therapy 2. Elevated troponin 3. New/dynamic ST-segment depression 4. Signs/symptoms of heart failure or new/worsening mitral regurgitation 5. High-risk findings from noninvasive testing 6. Hemodynamic instability 7. Sustained ventricular tachycardia (>30 s and/or hemodynamic instability) 8. PCI within 6 mo 9. TIMI risk score ≥3

10. Newly reduced left ve