Chapter 31: Acute Coronary Syndrome

This patient presents with acute ischemic stroke and myocardial infarction. There is evidence of hemodynamic deterioration; therefore, a decision regarding management of acute coronary syndrome (ACS) must be made quickly. Management of acute ischemic stroke is discussed in Chapter 5.

This patient presents with ECG and laboratory evidence of myocardial infarction. The initial ECG showed ST depressions anteriorly, which should alert the clinician to the possibility of posterior wall ST-segment elevation myocardial infarction. In this clinical scenario it would be appropriate to place “posterior” ECG leads, which can be accomplished by placing three electrodes—V₇, V₈, and V₉—in the left posterior axillary line at the fifth interspace, at the left midscapular line at the fifth interspace, and at the left paraspinal border at the fifth interspace, respectively. Significant ST elevation in leads V₇ through V₉ is defined as at least 0.5 mm in two or more of the leads, based on the increased distance between the posterior chest wall and the heart. Q waves wider than 0.04 second or deeper than one-quarter of the amplitude of the succeeding R wave are considered pathologic in leads V₇ through V₉.^{1, 2}

Acute coronary syndrome is a spectrum of clinical syndromes and includes unstable angina (UA), non–ST-segment-elevation myocardial infarction (NSTEMI), and ST-segment-elevation myocardial infarction (STEMI). Variant angina, also known as Prinzmetal angina, can manifest as ST-segment-elevation on the electrocardiogram and elevated serum troponin levels but is pathologically distinct from acute coronary syndrome. Although the pathogenesis and clinical presentation of UA and NSTEMI are similar, the presence of serum cardiac biomarkers, troponin I, or troponin T distinguishes NSTEMI from UA. In patients with NSTEMI, the degree of myocardial injury is severe enough to cause detectable serum levels of troponin I, troponin T, or CK-MB.

It is well established that coronary atherosclerosis is by far the most common cause of acute myocardial ischemia, with thrombosis as the trigger for myocardial infarction. Less common causes of myocardial ischemia include coronary artery dissection, coronary arteritis, coronary artery vaso-spasm, emboli, and rarely myocardial bridging. Until recently, the majority of our understanding of the mechanisms of conversion from chronic to acute coronary artery disease had largely been limited to postmortem data. In 1912, Dr. James Herrick published an autopsy study that associated the clinical presentation of acute infarction with a thrombotic coronary occlusion.³ Coronary artery occlusion resulting in acute coronary syndrome occurs by three mechanisms: thrombosis, plaque erosion, or plaque rupture. Plaque morphology described angiographically or via intravascular ultrasound or angioscopy has been instrumental in identifying atherosclerotic plaques that were more likely to cause acute coronary syndrome, the so-called vulnerable plaque. However, our understanding of the cellular and molecular mechanisms of how a vulnerable plaque develops is far from being complete.

Histopathologic and angioscopic studies have demonstrated that both plaque rupture and erosion leading to thrombosis are the most common causes of acute coronary syndrome. Plaques that are more likely to rupture are termed vulnerable plaques or thin-cap fibroatheromas. They are characterized as being eccentric, with a larger lipid core, fewer smooth muscle cells, and a greater number of macrophages.^{4, 5, 6} Plaque with a lipid core often contains oxidized lipids and macrophage-derived tissue factor, which makes the plaque highly thrombogenic when its contents are exposed to blood. This in turn activates the clotting cascade, as well as platelet adhesion, activation, and aggregation.⁷ It is thought that plaque rupture accounts for > 70% of fatal acute myocardial infarctions and/or sudden cardiac death. The smaller concentration of smooth muscle cells is thought to weaken the mechanical resistance of the plaque. Plaque rupture generally occurs where the plaque is thinnest and has the highest degree of inflammatory cells (ie, foam cells). In an eccentric plaque this typically occurs at the shoulder region, which is the junction between the plaque and the area of the vessel wall that is less diseased.⁸

Plaque erosion refers to a thin-cap fibroatheroma that literally develops a fissure or defect in the fibrous cap, thereby exposing the thrombogenic core to flowing blood.⁹ Erosions occur over plaques that are rich in smooth muscle cells and proteoglycans. Luminal thrombi occur in denuded areas lacking surface endothelium. Unlike plaques prone to rupture, plaques prone to erosion typically lack a necrotic core of lipid but rather are composed of macrophages and lymphocytes. Lastly, calcified nodules are plaques with luminal thrombi showing calcified nodules protruding into the lumen through a disrupted thin fibrous cap. There is absence of endothelium at the site of the thrombus as well as lack of inflammatory cells (macrophages and T lymphocytes). There is little or no necrotic core and typically there is no obvious rupture of the lesion. However, there are superficial, dense, calcified nodules within the intima, which appear to be erupting through fibrous tissue into the lumen, possibly causing the thrombus.¹⁰

Numerous postmortem studies have identified ruptured plaque as the cause of thrombosis in acute myocardial infarction. Richardson et al studied 85 coronary thrombi postmortem and found a disrupted atheromatous plaque beneath 71 (84%) of the thrombi.¹¹ Studies comparing coronary angiograms before and after the onset of the acute coronary syndrome confirmed that the majority of culprit lesions demonstrate a luminal stenosis of < 70% on the initial angiogram. However, the lesions with a less severe degree of luminal stenosis (< 50%) on the initial angiogram were more likely to be the cause of acute coronary syndrome.^{12, 13, 14, 15,16} The composition and vulnerability of plaque rather than its volume or the consequent severity of stenosis produced have emerged as being the most important determinants of the development of the thrombus-mediated acute coronary syndromes.⁸ In addition, both angiographic studies and intravascular ultrasound of plaque morphology in patients presenting with acute coronary syndrome have shown that multiple complex or ruptured plaques exist simultaneously. This implies a systemic process in the pathogenesis of plaque rupture.¹⁷ The relationship between systemic markers of inflammation and the acute coronary syndromes is beyond the scope of this chapter.¹⁸

The clinical presentation and outcome depend on the location, severity, and duration of myocardial ischemia. Unstable angina and NSTEMI are typically caused by partial coronary artery obstruction by a thrombus, while STEMI is caused by complete coronary artery obstruction. The clinical presentation can, of course, be mediated by other factors such as vascular tone or the presence of collaterals.¹⁹ It is noteworthy that many coronary arteries apparently occlude silently without causing myocardial infarction, probably because of a well-developed collateral circulation at the time of occlusion.²⁰ Morphological studies suggest that plaque progression beyond 40% to 50% cross-sectional luminal narrowing may occur secondary to repeated asymptomatic plaque ruptures, which may lead to healing with infiltration of smooth muscle cells.^{7, 18}

Acute coronary syndrome is not likely to occur at random. The first study that looked at external triggers of ACS such as time of day, occupation of the patient, and physical effort was published by Masters in 1960. It was a retrospective review of 2600 patients. Although the study lacked formal statistical analysis, it concluded that there was no link between such external triggers and the onset of ACS.²¹ In 2006, Strike et al performed a prospective observational study of 295 patients with electrocardiographic and biochemically verified ACS. Ten percent of patients reported physical exertion 1 hour before symptom onset, whereas 17.4% of patients reported anger in the 2 hours prior to symptom onset. Both types of triggers were more commonly associated with STEMI than with other forms of ACS.²² The possible link between physical or emotional stress and acute coronary syndrome is not well understood. Physical exertion and mental stress may have similar effects on cardiovascular functioning in that both can trigger an increase in heart rate, blood pressure, coronary vasoconstriction, plasma catecholamine levels, and platelet activation.²³ During exercise or periods of stress, there is activation of the sympathetic nervous system with subsequent release of norepinephrine from myocardial sympathetic nerves in addition to circulating epinephrine and norepinephrine. Sympathetic stimulation leads to α₁-mediated vasoconstriction and β₂-mediated vasodilatation. The net physiologic response is dilation of the epicardial coronary arteries and microvessels.²⁴ Patients with impaired endothelial function and clinical risk factors for coronary artery disease exhibit an enhanced α-adrenergic vasoconstriction. When nitric oxide endothelium–dependent vasodilatation is impaired, vasoconstriction predominates, which in turn increases shear stress at the atherosclerotic plaque. A possible consequence is plaque rupture at the shoulder region.^{25, 26, 27}

What has been described above is the pathogenesis of acute coronary syndrome due to plaque disruption. However, coronary angiography may demonstrate normal coronary arteries in patients with chest pain, ECG abnormalities, and/or positive cardiac biomarkers. There are five major causes of ACS: thrombus, mechanical obstruction, dynamic obstruction, inflammation, and increased oxygen demand.²⁸ Takotsubo syndrome, also known as broken heart syndrome, is defined as transient reversible left ventricular (LV) apical ballooning of acute onset without coronary artery stenosis that clinically mimics acute coronary syndrome. It is associated with typical chest pain and ECG changes consistent with ischemia or infarction. Tsuchihashi et al performed a multicenter retrospective review of 88 patients (12 men and 76 women), aged 67 ± 13 years, who fulfilled the following criteria: (1) transient LV apical ballooning, (2) no significant angiographic stenosis, and (3) no known cardiomyopathies. Chest pain occurred in 67% of patients, and 56% of patients had a significant elevation in creatine kinase; of the 43 patients who had troponin T measured, 72% of them had a significant elevation. Electrocardiogram findings included ST elevation (90%), Q waves (27%), T-wave inversion (44%). Fifteen percent of patients developed cardiogenic shock. All patients had angiogram-confirmed nonobstructive epicardial coronary arteries (stenosis < 50%). During cardiac catheterization, only 10 patients were found to have coronary vasospasm. Based on chart review, the authors concluded that 20% of patients had a recent psychological stressor, 7% had an associated neurogenic condition, and 33% had a recent minor or major physiologic stress such as surgery.²⁹

It has been proposed that stress-induced cardiomyopathy is a catecholamine-driven process. Wittstein et al performed a prospective study on 19 patients who presented with stress-induced cardiomyopathy. On hospital day 1 or 2, plasma levels of catecholamine among patients with stress cardiomyopathy were 2 to 3 times the values among patients with Killip class III myocardial infarction and 7 to 34 times the published normal values.³⁰

Other causes of acute coronary syndrome with normal coronary arteries include coronary artery embolism (eg, in patients with atrial fibrillation or prosthetic heart valves)³¹; coronary artery spasm (eg, in patients who abuse cocaine)³²; and spontaneous coronary artery dissection (eg, in pregnant and postpartum women).³³ See Table 31-1.

Patients with coronary artery spasm (CAS), also known as variant or Prinzmetal angina, present with chest pain and concomitant ST-segment elevation. Prolonged vasospasm can result in frank myocardial infarction. It is commonly seen in young people who abuse cocaine. However, more recent reviews suggest that vagal withdrawal is most often the mechanism leading to spontaneous CAS. Other mechanisms responsible for CAS include increased sympathetic tone, abnormal nitric oxide synthase in dysfunctional endothelium, and enhanced phospholipase C enzyme activity inducing focal smooth muscle cell sensitivity.^{34, 35, 36} Established therapies include calcium channel blockers, long-acting nitrates, and in rare intractable cases internal mammary artery grafting. CAS may be associated with life-threatening ventricular arrhythmias, which may be an indication for implantation of an automated defibrillator.³⁷

Acute coronary syndrome can present in varying ways. High-risk or probable high-risk chest pain is described as prolonged, lasting for more than 30 minutes, a pressure-like sensation, or chest heaviness with radiation to 1 or both shoulders or arms. It often occurs on exertion and is associated with nausea, vomiting, or diaphoresis.³⁸ However, a considerable proportion of patients who present with ACS do not have chest pain. The National Registry of Myocardial Infarction (NRMI) is a database to which 1674 US hospitals contribute data. Among patients with confirmed MI who were enrolled in the NRMI between 1994 and 1998, 33% (n = 142,445) had chest pain at the time of presentation to the hospital. Older patients, women, and diabetic patients were more likely to lack chest pain. Only 23% of patients without chest pain had ST elevation on the initial ECG.³⁹ Patients without chest pain but with myocardial infarction were less aggressively treated and had a 23.3% in-hospital mortality rate compared with 9.3% among patients with chest pain.³⁹ Other atypical symptoms such as dyspnea, nausea and vomiting, and syncope can be associated with ACS.

This patient has ST-segment depressions in V₁ through V₅. All patients with chest discomfort, anginal equivalent, or other symptoms consistent with ACS should have a 12-lead ECG within 10 minutes of arrival to the emergency department. An experienced physician should interpret the ECG immediately. Either serial ECGs at 5- to 10-minute intervals or continuous ST-segment monitoring should be performed in a patient with a nondiagnostic initial ECG if the patient remains symptomatic and there is high clinical suspicion for ACS. In patients with inferior STEMI, right-sided ECG leads should be obtained to screen for ST elevation suggestive of right ventricular infarction.⁴⁰ See Table 31-2.

Normally the ST segment on the ECG is at approximately the same baseline level as the PR segment or the TP segment. If coronary artery blood flow is sufficient to satisfy metabolic demands, then there is minimal alteration, if any, of the ST segment on the surface ECG. If there is partial obstruction of a coronary artery that prevents blood flow from increasing enough to meet the increased metabolic demand, the resulting ischemia is manifested by horizontal or downsloping ST-segment depression. This is typically called subendocardial ischemia. Often the ST segments return to normal once the metabolic demand has ceased. Hyperacute T waves might be the first manifestation of myocardial injury due to complete arterial occlusion. If the arterial occlusion persists without reperfusion, a myocardial infarction occurs and is represented as ST-segment deviation on the surface ECG.

This patient's electrocardiogram is consistent with posterior wall infarction. An ECG utilizing leads V₇, V₈, and V₉, which are placed on the posterior torso, would likely show ST-segment elevation. The standard 12-lead electrocardiogram is a relatively insensitive tool for detecting posterior infarction because these leads do not face the posterior wall of the left ventricle. Using leads V₇, V₈, and V₉, ECG criteria for ST elevation of the posterior wall is defined as an elevation of at least 0.5 mV in two or more of the leads. This lower voltage can be explained by the increased distance between the posterior chest wall and the heart.^{2, 41} Currently, the indications for thrombolytic therapy or percutaneous coronary intervention require identification of ST elevation on the standard 12-lead electrocardiogram. However, ST elevation may not be seen in up to 50% of patients with an MI because of occlusion of the left circumflex coronary artery.^{4, 42, 43} Suspicion of left circumflex–related infarction should occur if the standard 12-lead ECG shows an abnormal R wave in lead V₁, which may be defined as ≥ 0.04 seconds in duration and/or an R-to-S wave ratio of ≥ 1 in lead V₁ in the absence of preexcitation or right ventricular hypertrophy. In addition, the presence of anterior ischemia with ST-segment depression in leads V₁ and V₂ may suggest reciprocal electrical phenomena in the presence of a posterior infarction. Posterior wall infarction rarely occurs in isolation but rather is almost always associated with inferior or posterior lateral infarction. The term posterior to reflect the basal part of the LV wall that lies on the diaphragm is no longer recommended. It is preferable to refer to this territory as inferobasal.⁴⁴ In patients with ECG evidence of inferior wall MI, right-sided precordial leads should be recorded to detect ST-segment elevation in leads V₃R or V₄R, signs of right ventricular infarction.⁴⁵

The location of the infarcted area can usually be determined by the standard 12-lead electrocardiogram and includes the left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA). The LAD and its branches usually supply the anterior and anterolateral walls of the left ventricle and the anterior two-thirds of the septum. The LCX and its branches usually supply the posterolateral wall of the left ventricle. The RCA supplies the right ventricle, the inferior and true posterior walls of the left ventricle, and the posterior third of the septum. The usual ECG evolution of an STEMI is variable depending on the size of the MI, how quickly reperfusion is restored, and the location of the MI. See Table 31-3.

The first finding of ischemia on a 12-lead electrocardiogram can be hyperacute T waves, which appear as tall-amplitude primary T-wave abnormalities. These typically occur in the first 15 minutes of a transmural MI and therefore are rarely recorded. If transmural ischemia persists for more than a few minutes, the peaked T waves evolve into ST-segment elevation. The ST-segment elevation of myocardial infarction is usually upward convex. As acute infarction continues to evolve, the ST-segment elevation decreases and the T waves begin to invert. The T wave usually becomes progressively deeper as the ST-segment elevation subsides. Pathologic Q waves develop within the first few hours to days after an infarction. They are defined as having a duration ≥ 0.04 seconds or > 25% of the R-wave amplitude. However, ST-segment elevation that persists beyond 4 weeks is usually associated with the presence of a ventricular aneurysm.⁴⁶ See Table 31-3.

Typically the degree of ST elevation is determined by comparing it to the end of the PR segment. In certain populations, ST-segment elevation can be a normal finding or a normal variant. Early repolarization is an ECG finding that frequently occurs in young men and is described as an elevated takeoff of the ST segment at the junction between the QRS and ST segment (J point). It most commonly involves V₂ through V₅ but can be seen in II, III, and aVF. The ST segment is usually concave.^{47, 48}

Other causes of ST elevation not associated with acute myocardial infarction include left bundle branch block, left ventricular hypertrophy, acute pericarditis or myocarditis, Brugada syndrome, hyperkalemia, and arrhythmogenic right ventricular cardiomyopathy (Figure 31-4).

In the acute setting it is appropriate to consider 2-D echocardiography for the following indications: evaluation of acute chest pain with suspected myocardial ischemia in patients with nondiagnostic laboratory markers and ECG and in whom a resting echocardiogram can be performed during pain; and evaluation of suspected complications of myocardial ischemia or infarction, including but not limited to acute mitral regurgitation, hypoxemia, abnormal chest x-ray, ventricular septal rupture, free wall rupture, cardiac tamponade, shock, right ventricular involvement, heart failure, or thrombus.⁴⁹ A 2-D echocardiogram alone should not be used to diagnose an acute coronary syndrome. However, there are several echocardiographic findings that may support the diagnosis of an acute coronary syndrome. In the setting of acute ongoing ischemia the echocardiogram may demonstrate hypokinesis of the affected wall, referred to as a segmental wall motion abnormality. Often the contralateral wall will appear hyperkinetic. However, if a segment is akinetic, dyskinetic, or severely hypokinetic, a single echocardiogram cannot differentiate ischemia with myocardial stunning from irreversible damage due to myocardial necrosis.

A transesophageal echo may be helpful in differentiating acute myocardial infarction from aortic dissection. Mitral regurgitation commonly occurs in the setting of acute myocardial infarction. Color Doppler echocardiography was performed within 48 hours of admission in a series of 417 consecutive patients with acute MI.⁵⁰ Mild mitral regurgitation was present in 29% of patients, moderate mitral regurgitation in 5%, and severe mitral regurgitation in 1%. Echocardiography performed in a cohort of 773 patients 30 days after an acute MI revealed that 50% of patients had mitral regurgitation.⁵¹ Among 30-day survivors of an MI, during a mean follow-up period of 4.7 years, moderate to severe mitral regurgitation detected by echocardiography within 30 days of MI was associated with a 55% increase in the relative risk of death independent of age, gender, left ventricular ejection fraction, and Killip class.⁵¹

Myocardial infarction is defined as myocardial cell death as a result of prolonged myocardial ischemia. Cardiac troponin I and cardiac troponin T are the preferred biomarkers to confirm myocardial ische-mia. The cardiac troponin elevations begin 2 to 4 hours after onset of symptoms and may persist for several days beyond the initial event (Figure 31-5).

Cardiac troponin offers little incremental value in classic STEMI. A more extensively studied group in which troponin is very common are high-risk patients with ACS (NSTEMI or UA). Cardiac troponin T and cardiac troponin I are sensitive^{52, 53} markers of cardiac injury, particularly when used with the recommended⁵⁴ diagnostic cutoff point of the 99th percentile of healthy controls.^{55, 56} An elevation in serum cardiac troponin in this group helps direct the use of antithrombotic and antiplatelet therapy (both will be discussed later).

Frequently, patients with end-stage renal disease will have chronically elevated levels of troponin, making it difficult to determine its utility in acute coronary syndrome. Keeping in mind that the most common cause of death among patients with end-stage renal disease is cardiovascular, these patients should be regarded as high risk. Therefore, despite the difficulty in determining chronic versus acute troponin levels, patients with end-stage renal disease will likely benefit from a more aggressive antithrombotic and interventional approach.^{57, 58} Creatine kinase, CK-MB fraction, and myoglobin have largely fallen out of favor as biomarkers to diagnose myocardial infarction.

An elevated cardiac troponin level in the absence of overt ischemic heart disease is a common finding in both acute and nonacute processes. When serum cardiac troponin is present but the clinical information does not suggest ACS, the clinician should look for other causes. See Table 31-4.

It is not uncommon for patients who are critically ill in the ICU to have concomitant ACS. Continuous ECG monitoring is a key component to early detection and treatment of ACS in the critical care unit. This patient's ECG shows ST elevation in the inferior leads. Given that she recently had a drug-eluting stent placed for inferior wall MI, the clinician should immediately be concerned about subacute stent thrombosis. Since this patient presented with a hemorrhagic thalamic stroke, it is likely that antiplatelet agents such as aspirin and clopidogrel were appropriately held at admission. ST can occur acutely (within 24 hours), subacutely (within 30 days), late (within 1 year), or very late (beyond 1 year). According to the American College of Cardiology (ACC)/American Heart Association (AHA) 2007 Guidelines on Management of Patients with UA/NSTEMI, patients treated with bare-metal stents should remain on aspirin 162 to 325 mg/d and clopidogrel 75 mg/d for a minimum of 1 month and ideally for up to 1 year (class I recommendation).⁵⁹ For patients with UA/NSTEMI who are treated with a drug-eluting stent, aspirin 162 to 325 mg/d should be prescribed for at least 3 months after sirolimus-eluting stent implantation and for at least 6 months after paclitaxel-eluting stent implantation. Subsequently, aspirin should be continued indefinitely at a dose of 75 to 162 mg/d (class I recommendation). Clopidogrel 75 mg daily should be given for at least 12 months to all patients receiving drug-eluting stents after percutaneous coronary intervention (PCI) (class I recommendation).⁵⁸ This patient should be treated with aspirin, clopidogrel, and the appropriate anticoagulant when the neurologist deems it to be safe.

The frequency of stent thrombosis is greatest within 30 days after stent placement. The Dutch Stent Thrombosis Registry enrolled 1009 patients who received either a bare-metal or drug-eluting stent. Among 437 patients (2.1%) who presented with a definite stent thrombosis, 140 stent thromboses were acute, 180 were subacute, 58 were late, and 59 were very late. Along with several technical aspects of stent deployment, lack of aspirin, bifurcation lesions, ejection fraction < 30%, and younger age were associated with stent thrombosis. The lack of clopidogrel therapy at the time of stent placement in the first 30 days after the index PCI was strongly associated with stent thrombosis (hazard ratio: 36.5; 95% confidence interval [CI]: 8.0-167.8).⁶⁰ In a substudy of the ACUITY trial published in 2009, the incidence of angiographically confirmed subacute stent thrombosis in 3405 moderate- and high-risk patients with acute coronary syndromes receiving stents (89.4% drug-eluting stents) was 1.4%.⁶¹ Patients with acute and subacute stent thrombosis often present with STEMI. Immediate PCI is the treatment of choice if available. However, fibrinolytic therapy is also an option. Unfortunately, patients who have STEMI due to stent thrombosis have worse outcomes when compared with patients with STEMI due to de novo plaque rupture. One retrospective study showed that the successful reperfusion rate was lower in patients with stent thrombosis and the distal embolization rate was higher in patients with stent thrombosis when compared with patients with de novo plaque rupture.⁶² In one real-world-experience study of 23,500 patients treated with drug-eluting stent, definite stent thrombosis developed in 301 (1.3%) and the mortality at 1-year follow-up was 16%.⁶³

Oxygen

The body of literature regarding the use of supplemental oxygen in uncomplicated acute MI is small. In one small randomized controlled study in which 200 patients received either supplemental oxygen or compressed air, the mortality rate was higher in the oxygen group than in the control group (9/80 versus 3/77; PS = NS).⁶⁴ According to the ACC/AHA guidelines, the only class I indication for supplemental oxygen is if the patient's arterial saturation is < 90%. It is a class IIa indication to administer supplemental oxygen in the first 6 hours of an uncomplicated STEMI.⁴⁰

Analgesics

Morphine sulfate (2-4 mg intravenously [IV] with increments of 2-8 mg IV repeated at 5- to 15-minute intervals) is the analgesic of choice for management of pain associated with ACS and is considered a class I indication according to the most recent ACC/AHA guidelines.⁴⁰ To date, there are no published randomized controlled trials that evaluate the use of morphine therapy in patients with acute MI. However, as a means of decreasing sympathetic tone during pain, morphine may be a useful agent in reducing the heart's metabolic demand. The CRUSADE Initiative, a nonrandomized, retrospective, observational registry, evaluated various therapies in over 17,000 patients presenting with non-STEMI. It showed that 29.8% of patients received morphine within 24 hours of presentation. Patients treated with any morphine had a higher adjusted risk of death (odds ratio [OR]: 1.48; 95% CI: 1.33-1.64) than patients not treated with morphine.⁶⁵

Nitrates

Both intravenous and sublingual nitroglycerin are often used in the management of ACS.

According to the most recent ACC/AHA guidelines, there are two class I indications for the use of nitrates in an STEMI: (1) patients with ongoing ischemic discomfort should receive sublingual nitroglycerin, 0.4 mg every 5 minutes for a total of three doses, after which an assessment should be made about the need for intravenous nitroglycerin; and (2) intravenous nitroglycerin is indicated for relief of ongoing ischemic discomfort, control of hypertension, or management of pulmonary congestion.⁴⁰ Nitroglycerin has many beneficial physiologic effects, including vasodilation of peripheral arteries and veins and a reduction in pulmonary capillary wedge pressure, mean arterial pressure, and peripheral vascular resistance. The ultimate outcome is a decrease in myocardial oxygen demand. However, nitroglycerin should be used with caution in certain patients. Nitrates and other drugs that reduce preload should be avoided in patients with right ventricular infarction because adequate preload is necessary to maintain cardiac output. In addition, nitrates can produce severe hypotension in patients who have taken a phosphodiesterase inhibitor recently.⁶⁶ Generally, nitrates should not be administered to patients with systolic blood pressure below 90 mm Hg or 30 mm Hg below the baseline or if there is marked bradycardia or tachycardia.⁶⁷ Nitrates have not been shown to reduce mortality in patients with acute MI. The Fourth International Study of Infarct Survival (ISIS-4) enrolled 58,050 patients with suspected acute MI within 24 hours of presentation. Patients were randomized in a 2 × 2 × 2 fashion to an angiotensin-converting enzyme (ACE) inhibitor, magnesium, and 30 mg of oral mononitrate titrated to 60 mg daily or placebo for 28 days. Oral nitrates failed to produce a mortality benefit at 5 weeks or 1 year.⁶⁸ Similar findings were noted in the Gruppo Italiano per lo Studio della Sopravvivenza nell' infarto Miocardico-3 (GISSI-3) trial, which enrolled 19,394 patients with acute MI and randomized them to 6 weeks of nitrates, an ACE inhibitor, both, or neither. Nitrates were administered as IV glyceryl trinitrate for the first 24 hours, followed by transdermal or oral isosorbide mononitrate for 6 weeks. Nitroglycerin did not reduce the 6-week rates of death or clinical heart failure after MI.⁶⁹

Aspirin

The efficacy of aspirin in patients with ACS is well established. Several different doses of aspirin have been shown to reduce mortality rate and vascular events in patients with ACS. The ISIS-2 trial demonstrated a 23% reduction in 5-week vascular mortality rate among patients with acute MI who were treated with aspirin 160 mg daily.⁷⁰ The absolute mortality reduction was 2.4 vascular deaths prevented per 100 patients treated. The Veterans Administration Cooperative Study demonstrated a 51% reduction in the principal end points of death and acute myocardial infarction at 12 weeks among patients with UA/NSTEMI who were randomized to 325 mg of aspirin daily.⁷¹ A review of 4000 patients with unstable angina who were enrolled in randomized trials of aspirin versus placebo demonstrated a 5% absolute risk reduction in nonfatal stroke or MI or vascular death (9% versus 14%). This corresponds to 50 vascular events avoided per 1000 patients treated with aspirin for 6 months.⁷² A recent trial randomized 25,087 patients with ACS (29.2% STEMI and 70.8% unstable angina or NSTEMI) to either low-dose aspirin (75-100 mg/d) or high-dose aspirin (100-325 mg/d). There was no significant difference between the two groups in either efficacy or bleeding. The current ACC/AHA practice guidelines recommend an initial aspirin dose of 162 to 325 mg followed by a maintenance dose of 75 to 162 mg daily.^{40, 59}

Experimental data suggest that β blockers have several immediate beneficial physiologic effects during acute MI. The reduction in heart rate, systemic arterial pressure, and myocardial contractility may diminish myocardial oxygen demand in the first few hours of onset of acute MI. The benefit of β blocker therapy, either early or delayed, in ACS has been well described. A pooled analysis of 27 randomized trials indicated that early β blockade reduced mortality rate by 13% in the first week, with the greatest reduction in mortality rate occurring in the first 2 days.⁷³ The Thrombolysis in Myocardial Infarction (TIMI)-IIB study randomized 1434 patients who received tissue plasminogen activator (tPA) for acute STEMI to either immediate or deferred β blockade. Patients randomized to immediate therapy received three doses of 5 mg IV metoprolol, followed by 50 mg twice a day on day 1, then 100 mg twice a day. Patients randomized to deferred therapy received oral metoprolol 50 mg twice a day on day 6 followed by 100 mg twice a day thereafter. Overall, there was no difference in mortality rate between the immediate intravenous and deferred groups. However, there was a lower incidence of reinfarction (2.7% versus 5.1%; P = .02) and recurrent chest pain (18.8% versus 24.1%; P < .02) at 6 days in the immediate intravenous group.⁷⁴ A post-hoc analysis of the use of atenolol in the Global Utilization of Streptokinase and TPA for Occluded Arteries-1 (GUSTO-1) trial reported that adjusted 30-day mortality rate was significantly lower in atenolol-treated patients, but patients treated with intravenous and oral atenolol treatment versus oral treatment alone were more likely to die (OR: 1.3; 95% CI: 1.0-1.5; P = .02).⁷⁵

The Clopidogrel and Metoprolol in Myocardial Infarction Trial-2 (COMMIT-CCS 2) of 45,852 patients with acute MI showed an increased risk of developing heart failure and cardiogenic shock in patients randomized to β-blocker therapy.⁷⁶ Patients were randomized to treatment with metoprolol (three intravenous injections of 5 mg each followed by 200 mg/d orally for up to 4 weeks) or placebo. Ninety-three percent of patients had STEMI and approximately 54% of patients received a fibrinolytic agent. There was no difference in the primary end point of death, reinfarction, or cardiac arrest by treatment group (9.4% for metoprolol versus 9.9% for placebo; P = NS). There was also no difference in the coprimary end point of all-cause mortality rate by hospital discharge (7.7% versus 7.8%; P = NS). Reinfarction was lower in the metoprolol group (2.0% versus 2.5%; P = .001). Death due to shock occurred more frequently in the metoprolol group (2.2%, n = 496, versus 1.7%, n = 384), while death due to arrhythmia occurred less frequently in the metoprolol group (1.7%, n = 388, versus 2.2%, n = 498). Cardiogenic shock was higher overall in the metoprolol group (5.0%, n = 1141, versus 3.9%, n = 885; P < .0001).⁷⁶

Although acute oral β-blocker use in patients with STEMI undergoing fibrinolytic therapy or primary PCI is still a class I indication, the 2007 ACC/AHA Focused Update of the STEMI Guidelines downgraded it from the level of evidence A to the level of evidence B. Additionally, IV β blockers are no longer recommended in the absence of systemic hypertension.⁷⁷ The following relative contraindications should be considered before initiating β-blockers: heart rate < 60 bpm, systolic arterial pressure < 100 mm Hg, moderate or severe LV failure, signs of peripheral hypoperfusion, shock, PR interval > 0.24 second, second- or third-degree atrioventricular (AV) block, active asthma, and reactive airway disease.⁷⁷ β Blockers should not be administered to patients with cocaine-associated STEMI, because β blockade might exacerbate coronary artery vasospasm. β Blockers are contraindicated in patients with STEMI complicated by cardiogenic shock or severe left ventricular dysfunction.

In contrast to the use of early, aggressive β-blocker therapy, the long-term use of β blockers after occurrence of MI has favorable outcomes on mortality. The Carvedilol Post-infarct Survival Controlled Evaluation (CAPRICORN) trial was a randomized, placebo-controlled trial designed to test the long-term efficacy of carvedilol on morbidity and mortality in patients with LV dysfunction 3 to 21 days after MI who were already treated with ACE inhibitors. After an average follow-up period of 1.3 years, cardiovascular mortality was lower in the carvedilol arm (11% versus 14% for placebo; hazard ratio: 0.75; P = .024), as was all-cause mortality or nonfatal MI (14% versus 20%; hazard ratio: 0.71; P = .002).⁷⁸ This study supports the claim that β-blocker therapy after acute MI reduces mortality irrespective of reperfusion therapy or ACE inhibitor use.

Calcium channel antagonists vary in the degree to which they produce vasodilation, decreased myocardial contractility, AV block, and sinus node slowing. Nifedipine and amlodipine have a greater effect on peripheral vasodilation, whereas verapamil and diltiazem have a greater effect on AV node and sinus node inhibition. Currently, there is no class I indication for the use of calcium channel antagonists in acute MI because there has been no proven mortality benefit demonstrated in individual clinical trials or pooled analyses.^{79, 80} There are two class III recommendations for the use of calcium channel antagonists in acute MI: (1) diltiazem and verapamil are contraindicated in patients with STEMI and associated systolic left ventricular dysfunction and congestive heart failure (CHF); and (2) nifedipine (immediate-release form) is contraindicated in the treatment of STEMI because of the reflex sympathetic activation, tachycardia, and hypotension associated with its use.⁴⁰

All patients with STEMI who present within 12 hours of symptom onset should be considered for reperfusion therapy with either fibrinolytics or PCI, with or without stent deployment. Early, complete, and sustained reperfusion after myocardial infarction is known to decrease 30-day mortality.

The preferred method for reperfusion in STEMI is PCI if it can be done in a timely manner. Early recognition and diagnosis of STEMI are key to achieving the desired door-to-needle (or medical contact–to-needle) time for initiation of fibrinolytic therapy of 30 minutes or door-to-balloon (or medical contact–to-balloon) time for PCI of < 90 minutes.⁸¹ In patients receiving fibrinolysis, careful surveillance over the first 1 to 3 hours is critical to ensure that successful reperfusion occurs, as indicated by relief of symptoms and/or any hemodynamic or electrical instability, coupled with at least 50% resolution of the initial ST elevation. Achieving reperfusion in a timely manner correlates with improvement in ultimate infarct size, left ventricular function, and survival.^{82, 83, -84} The ultimate goals are to restore adequate blood flow through the infarct-related artery to the infarct zone and to limit microvascular damage and reperfusion injury. The latter is accomplished with adjunctive and ancillary treatments, which will be discussed later.

Currently used fibrinolytic drugs are intravenously infused plasminogen activators that activate the blood fibrinolytic system. There are several well-known fibrinolytics with established efficacy for reducing short- and long-term mortality rate in patients with STEMI. The first large-scale trial to test thrombolytics was GISSI-1. In this trial, 11,712 patients were randomized to streptokinase or no treatment within 12 hours of presenting with acute MI. There was an 18% relative reduction in 21-day mortality rate for patients receiving streptokinase compared to placebo (10.7% versus 13%; P = .0002). The mortality benefit was greatest in the first hour. There was no difference in mortality when patients were treated beyond 6 hours.⁸⁵ Alteplase, recombinant tPA, is fibrin-specific. Fibrin-bound tPA has increased affinity for plasminogen, whereas unbound tPA in the systemic circulation does not extensively activate plasminogen.⁸⁶ GISSI-2 and ISIS-3 failed to demonstrate increased efficacy of alteplase over streptokinase.^{87, 88} The GUSTO-1 trial compared the effects of accelerated tPA with streptokinase on mortality in patients with acute MI. Forty-one thousand patients with acute MI who presented to more than 1000 hospitals within 6 hours of symptom onset were randomized to streptokinase plus either subcutaneous or intravenous heparin; accelerated alteplase with intravenous heparin; or a combination of streptokinase and alteplase.⁸⁹ There was a 14% reduction in mortality rate for accelerated tPA compared to the two streptokinase regimens (P = .001). The combined end point of death or disabling stroke was significantly lower in the accelerated tPA group (6.9%) than in the streptokinase groups (7.8%; P = .006).⁸⁹ The rate of stroke was 1.4%, which included intracerebral hemorrhage in 0.7%.⁹⁰

A third agent, reteplase, is less fibrin-selective and has a longer half-life than alteplase. The GUSTO-3 trial enrolled 15,059 patients with acute MI and randomized them to either reteplase or alteplase. The average time from symptom onset to treatment with either drug was 2.7 hours. There was no significant difference between the two drugs in mortality rate, the incidence of stroke, or the combined end point of death or nonfatal, disabling stroke.⁹¹ A follow-up study revealed that there was no difference in mortality rate at 1 year (11.2% versus 11.1%).⁹²

Tenecteplase (TNK-tPA) is a genetically engineered fibrinolytic agent that has a longer plasma half-life and is 14 times more specific for fibrin. The ASSENT-2 trial directly compared tenecteplase with alteplase in 16,949 patients. At 30 days, there was no difference in mortality rate, the overall stroke rate, or the rate of intracerebral hemorrhage. The mortality rate at 1 year remained the same with the two agents (10.2%). The incidences of stroke were similar in the two treatment groups, with 1.78% occurring in the TNK-tPA group and 1.66% in the tPA group (P = .55).⁹³

It is well established that patients who receive fibrinolytics within 1 hour of symptom onset, the so-called golden hour, derive the greatest mortality benefit.⁹⁴ All of the trials suggest that treatment beyond 12 hours confers no mortality benefit. Two large-scale randomized multicenter trials, LATE and Estuido Multicentrico Estrepoquinasa Republicass de Americas del Sur (EMARAS), evaluated the value of late thrombolysis, given 6 to 24 hours after the onset of symptoms.^{95, 96} In both studies, thrombolytics given at 12 to 24 hours showed no mortality benefit. The Fibrinolytic Therapy Trialist's Collaborative Group performed a meta-analysis of all randomized thrombolytic trials for suspected acute myocardial infarction enrolling 1000 or more patients. There was an 18% relative reduction in mortality rate to 35 days in the fibrinolytic-treated patients compared with controls (9.6% versus 11.5%; P < .00001) (Figure 31-7). Significant treatment benefit was seen up to 12 hours, but not in patients presenting more than 12 hours after symptom onset. Mortality rate reduction with thrombolytic therapy was demonstrated in all age groups except those aged 75 years or older. Fibrinolytic therapy was associated with a small but significant increase in strokes (1.2% versus 0.8%; P < .00001).⁹⁷ See Table 31-5.

Absolute and relative contraindications should be considered prior to initiating fibrinolytic therapy (Table 31-6). Intracranial hemorrhage is the major risk factor associated with fibrinolytic therapy. In GUSTO-1, the largest fibrinolytic study, there was a 1.8% risk of severe bleeding, defined as bleeding that caused hemodynamic compromise that required treatment. Also, 11.4% of patients suffered moderate bleeding, defined as bleeding that required blood transfusion but did not lead to hemodynamic compromise requiring intervention. The most common source of bleeding was related to procedures such as coronary angiography (17%), pulmonary artery catheter insertion (43%), and intra-aortic balloon pump placement (50%).⁹⁸ The NRMI-2 database accrued 71,073 patients who received reperfusion therapy for acute MI between 1994 and 1996. High-risk patients with ST-segment elevation were treated with thrombolytics (47.5%) or alternative forms of reperfusion therapy (9.3%) within 62 minutes and 226 minutes of hospital arrival, respectively. Intracranial hemorrhage was confirmed by computed tomography (CT) or magnetic resonance imaging in 625 patients (0.88%).⁹⁹ Several studies have proposed predictive models that assess the risk for intracranial hemorrhage (ICH) in patients receiving thrombolytic therapy. The following risk factors are associated with a higher incidence of ICH: older age, female gender, systolic pressure > 160 mm Hg, diastolic pressure > 95 mm Hg, prior stroke, and excessive anticoagulation.^{99, 100, 101, 102}

Major limitations of fibrinolytic therapy are incomplete reperfusion or reocclusion of the infarct-related artery. Reperfusion of the infarct-related artery is determined angiographically and flow is categorized as 1 of 4 TIMI grades: grade 0 is complete occlusion, grade 1 is penetration of contrast material without distal perfusion, grade 2 is delayed perfusion of the entire artery, and grade 3 is normal flow. Initial reperfusion may be unsuccessful in as many as 20% of patients. Failure to achieve adequate reperfusion is associated with markedly increased mortality rate.^{103, 104, 105} The original TIMI trial revealed that only 31% of occluded arteries were patent after administration of intravenous streptokinase.¹⁰³ In a substudy of GUSTO-1, 2431 patients underwent coronary angiography to assess patency of the infarct-related artery. Ninety minutes after initiation of accelerated tPA, 54% patients achieved adequate patency of the infarct-related artery as defined by TIMI grade 3 flow, compared to 31% of patients who received streptokinase plus unfractionated heparin (UFH).¹⁰³ Despite achieving TIMI grade 3 flow after fibrino-lytic therapy, clinical outcomes and survival are related to the speed of epicardial flow and the state of myocardial perfusion. After rupture of a vulnerable plaque, the local milieu becomes rich in tissue factor, which subsequently activates the coagulation cascade and promotes platelet activation and aggregation. Ancillary anticoagulation therapy in patients with STEMI who do or do not receive reperfusion therapy acts to establish and maintain patency of the infarct-related artery. See Table 31-7.

Much of the evidence supporting the use of glycoprotein IIb/IIIa antagonists in STEMI was generated before dual-antiplatelet therapy (aspirin plus a thienopyridine) was routinely administered to patients with STEMI. The results of recent clinical trials have raised questions regarding the utility of glycoprotein IIb/IIIa antagonists in addition to dual-antiplatelet therapy in patients with STEMI.^{106, 107, 108} Based on these trials, the 2009 Joint STEMI/PCI Focused Update Recommendations assigned a class IIa recommendation to glycoprotein IIb/IIIa receptor antagonists (abciximab, tirofiban, eptifibatide) at the time of primary PCI (with or without stenting) in selected patients with STEMI. However, administration of a glycoprotein IIb/IIIa antagonist before patient arrival in the cardiac catheterization laboratory, referred to as upstream administration, received a class IIb recommendation.⁸¹

Clopidogrel is an adenosine diphosphate receptor antagonist, a class of oral antiplatelet agents that block the P2Y₁₂ component of the adenosine diphosphate receptor and thus inhibit the activation and aggregation of platelets. A newer thienopyridine, prasugrel, was studied in the TRITON-TIMI 38 trial, which is discussed later in the text. Two randomized controlled trials, COMMIT-CCS 2 and CLARITY-TIMI 28, sought to determine the benefit of clopidogrel in combination with aspirin in patients with STEMI. CLARITY-TIMI 28, a trial sponsored by the manufacturer of clopidogrel, randomized 3491 patients who presented with STEMI within 12 hours of symptom onset to either clopidogrel (300 mg loading dose followed by 75 mg daily) or placebo. All patients received a fibrinolytic agent, aspirin, and when appropriate, heparin. Angiography was performed in 94% of patients a median of 84 hours after randomization. The primary end points consisted of patency of the infarct-related artery on angiography and death or recurrent MI before angiography. The incidence of this end point was significantly lower in the recipients of clopidogrel than in the recipients of the placebo (15% versus 22%). This difference was mostly a result of a difference in occlusion of the infarct-related artery (12% versus 18%). There was no difference in the rates of mortality or major bleeding between the two groups. COMMIT-CCS 2 randomized over 45,000 patients presenting with STEMI to either clopidogrel 75 mg daily plus 162 mg of aspirin or placebo plus aspirin 162 mg. Ninety-three percent of patients had ST-segment elevation or bundle branch block. Fifty-four percent of patients received fibrinolytics, and 3% underwent PCI. Compared to aspirin alone, dual-therapy recipients had significantly lower 30-day incidences of the primary composite end point of death, reinfarction, and stroke (9.2% versus 10.1%) and of death alone (7.5% versus 8.1%). A subgroup analysis revealed that the primary–end point benefit was restricted to recipients of fibrinolytic therapy. The incidence of major bleeding was about 0.6% in each group.¹⁰⁹ The 2009 Joint STEMI/PCI Focused Update Recommendations assigned a class I recommendation to administration of the loading dose of a thienopyridine in patients with STEMI for whom PCI is planned. Either of the following regimens was recommended: 300 to 600 mg of clopidogrel administered as early as possible before or at the time of primary or nonprimary PCI, or prasugrel 60 mg administered as early as possible before primary PCI. In patients with STEMI with a prior history of stroke and transient ischemic attack for whom primary PCI is planned, prasugrel is not recommended as part of a dual-antiplatelet therapy regimen (class III recommendation).⁸¹ Clopidogrel 75 mg daily or prasugrel 10 mg daily for at least 12 months is a class I recommendation for patients with ACS who receive bare-metal or drug-eluting stents.⁸¹

Fondaparinux is the preferred anticoagulant for patients with STEMI who do not receive reperfusion therapy. Otherwise, the recommendations included in the ACC/AHA guidelines apply to patients who do not receive reperfusion therapy; however, these patients have a higher risk for future adverse events.

Fibrinolytic therapy is given to eligible patients if primary PCI cannot be performed in a timely fashion. Otherwise, PCI is the preferred method of reperfusion in patients with STEMI. Approximately 30% of patients presenting with STEMI have a contraindication to fibrinolytic therapy. Primary PCI has been compared with fibrinolytic therapy in more than 20 randomized trials. A meta-analysis of 23 randomized trials that directly compared percutaneous transluminal coronary angiography (PTCA) with fibrinolytic therapy in patients with STEMI concluded that primary PTCA was better than thrombolytic therapy at reducing overall short-term death (7% versus 9%; P = .0002), nonfatal reinfarction (3% versus 7%; P < .0001), stroke (1% versus 2%; P = .0004), and the combined end point of death, nonfatal reinfarction, and stroke (8% versus 14%; P < .0001).¹¹⁰ However, the studies included in this meta-analysis were very heterogeneous in design and balloon angioplasty was the predominant method of PCI. High-risk patients, such as those with cardiogenic shock or anterior STEMI, seem to derive the greatest mortality benefit of PTCA versus fibrinolytic therapy.^{111, 112, 113, 114}

The DANAMI-2 trial randomized more than 1000 patients with STEMI and duration of symptoms < 12 hours (mean: 105 minutes) to either alteplase or PCI with stenting (93% of patients received stents). Patients who presented to non–PCI-capable facilities were transferred to a PCI-capable facility within 3 hours. The primary end point of mortality, reinfarction, or stroke at 30 days was significantly lower in the primary PCI group (8.0% versus 13.7%), prompting early termination of the study. This net benefit observed in the PCI group was largely driven by a strikingly lower rate of reinfarction in the PCI group (1.6% versus 6.3%; P < .001).¹¹⁵

The incidence of disabling stroke in the fibrinolytic and PCI groups was 2.0% versus 1.1% (P = .15), respectively. A subgroup analysis that risk-stratified patients according to TIMI risk score concluded that the mortality benefit of PCI was confined to high-risk patients (TIMI score ≥ 5).¹¹⁶ A 3-year follow-up study demonstrated that the composite end point (death, clinical reinfarction, and disabling stroke) was reduced by PCI compared with fibrinolysis (19.6% versus 25.2%; P = .006).¹¹⁷ Based on the current data, it is an ACC/AHA class I recommendation that patients with STEMI presenting to a hospital with PCI capability should be treated with primary PCI within 90 minutes of first medical contact. Patients with STEMI who present to a hospital without PCI capability and who cannot be transferred to a PCI center and undergo PCI within 90 minutes of first medical contact should be treated with fibrinolytic therapy within 30 minutes of hospital contact unless fibrinolytic therapy is contraindicated.⁷⁷

In the absence of reperfusion, angiographic studies of patients with STEMI suggest that occlusion of the infarct-related artery is present in 87% of patients at 4 hours, 65% at 12 to 24 hours, and 45% at 1 month after symptom onset.¹¹⁸ Many patients with acute MI present to medical facilities more than 12 hours after the onset of symptoms. The late open artery hypothesis proposes that late opening of an occluded infarct-related artery may reduce adverse LV remodeling. However, despite modest improvement in LV function after late opening of an infarct-related artery, randomized clinical trials have not demonstrated a reduction in hard clinical outcomes such as death, recurrent MI, stroke, or New York Heart Association class IV heart failure among patients who underwent PCI 3 to 28 days after having an MI.^{119, 120120, 121} The 2007 ACC/AHA updated STEMI guidelines assigned a class IIa recommendation to performing PCI in a patent infarct-related artery more than 24 hours after STEMI. It is not recommended to perform PCI of a totally occluded infarct-related artery more than 24 hours after STEMI in asymptomatic patients with 1- or 2-vessel disease if they are hemodynamically and electrically stable and do not have evidence of severe ischemia.⁷⁷

Patients who receive fibrinolytic therapy should be transferred immediately to the nearest PCI center. Reperfusion after administration of a fibrinolytic agent is assessed clinically and electrographically. Resolution of ST-segment elevation ≥ 50% and resolution of chest pain provide evidence of successful reperfusion after fibrinolytic therapy. However, fibrinolytic-treated patients with STEMI who meet high-risk criteria such as cardiogenic shock, hemodynamic or electrical instability, or persistent ischemic symptoms should be considered for rescue PCI (Figure 31-8). In contrast, facilitated PCI, defined as either a full dose of a fibrinolytic drug or a half-dose of a fibrinolytic drug plus a GpIIb-IIIa antagonist before planned PCI, is not recommended because it has been associated with increases in mortality rate, nonfatal reinfarction, urgent target lesion revascularization and stroke, and a trend toward a higher rate of major bleeding.^{122, 123, 124}

This patient is having an NSTEMI as defined by her symptoms, ECG findings, and elevated troponin I level. Treatment algorithms are the same for NSTEMI and UA, with the former being defined as having an elevated serum troponin I or T level. A number of risk assessment tools have been developed to assist in assessing the risk of death and ischemic events in patients with UA/NSTEMI, thereby providing a basis for therapeutic decision making. The TIMI risk score incorporates 7 risk indicators into a predictive model for the composite end points, all-cause mortality, new or recurrent MI, or severe recurrent ischemia prompting urgent revascularization within 14 days. It has been validated in the TIMI 11B trial and two separate cohorts of patients who were enrolled in the Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave Myocardial Infarction (ESSENCE) trial.^{125, 126} The TIMI risk calculator can be accessed at www.timi.org. Other risk models, the GRACE score and PURSUIT, have been designed and validated.^{127, 128, 129} The GRACE score can be accessed at www.outcomes-umassmed.org/grace and can be used at the bedside to determine the probability of in-hospital death as well as death and/or MI at 6 months. A higher GRACE score may prompt the clinician to employ an early invasive strategy. See Table 31-8.

Yes. Dynamic ECG changes are highly suggestive of acute ischemia. Importantly, transient ST-segment changes (≥ 0.5 mV) that develop during a symptomatic episode at rest and that resolve when the patient becomes asymptomatic strongly suggest acute ischemia and a very high likelihood of underlying severe coronary artery disease (CAD).⁵⁹ A completely normal ECG in a patient with chest pain does not exclude the possibility of ACS. Both ST-segment depression and T-wave inversion may be signs of myocardial ischemia. The amount of ST-segment depression or elevation is measured relative to the TP segment (the end of the T wave to the beginning of the P wave). It has been proposed that isolated ST-segment depression ≥ 1 mm measured at 80 milliseconds of the J point in ≥ 6 leads is 96.5% specific for acute MI.¹³⁰ A comprehensive differential diagnosis of the causes of ST-segment depression and T-wave inversion is listed in Table 31-9.

The early conservative strategy refers to maximal medical therapy with anti-ischemic and antithrombotic agents, followed by an exercise test, usually with myocardial perfusion imaging, in patients who do not have recurrent symptoms. Patients with inducible ischemia are scheduled for a cardiac catheterization if there are no contraindications. The early invasive strategy entails both maximal medical therapy and early cardiac catheterization and possible revascularization within 48 hours of presentation. Several randomized trials have directly compared the early invasive strategy with the early conservative strategy in patients with UA/NSTEMI and have demonstrated better short-term and long-term outcomes in patients randomized to the early invasive strategy. The Fragmin and Fast Revascularization during Instability in Coronary Artery Disease III (FRISC II),¹³¹ TACTICS-TIMI 18,¹³² and Randomized Intervention Trial of Unstable Angina III (RITA III)¹³³ trials each demonstrated that the composite end point of death, MI, and refractory angina was less frequent among patients who were randomized to the early invasive strategy, with the greatest benefit observed in high-risk patients. High-risk features include elevated serum troponin levels; the extent of ST-segment depression and the number of leads with ST-segment depression; age older than 65 years; recurrent angina or ischemia despite intensive anti-ischemic therapy; recurrent angina or ischemia with CHF or new or worsening mitral regurgitation; a high-risk noninvasive stress test; left ventricular ejection fraction < 40%; hemodynamic instability; sustained ventricular tachycardia; PCI within the past 6 months; and prior coronary artery bypass graft (CABG) surgery.⁵⁹

The ICTUS trial enrolled 1200 patients with UA/NSTEMI who were initially treated with aspirin and enoxaparin before randomized assignment to one of two strategies: an early invasive strategy within 48 hours that included abciximab for PCI or a selective invasive strategy. Patients who were assigned the latter strategy were selected for coronary angiography only if they had refractory angina despite medical treatment, if they had hemodynamic or rhythm instability, or if predischarge exercise testing demonstrated clinically significant ischemia. The trial failed to show a reduction in the composite end points of death, nonfatal MI, and rehospitalization for angina at 1 year among patients who were assigned to the early invasive strategy. After 4 years of follow-up, the rates of death and MI among the two groups of patients remained similar.¹³⁴ It is not clear why the results of ICTUS differ so much from previous trials. The more recent Timing of Intervention in Acute Coronary Syndromes (TIMACS) study randomized 3031 patients with UA/NSTEMI to undergo cardiac catheterization either within 24 hours of symptom onset or more than 36 hours later.¹³⁵ The median time to angiography was 14 hours for the early-intervention group and 50 hours for the delayed-intervention group. There was no difference between the groups in the composite end point of death, myocardial infarction, and stroke at 6 months.¹³⁵ The most recent guidelines regarding an early invasive versus conservative strategy in patients with UA/NSTEMI are listed in Table 31-10. An early invasive strategy (ie, diagnostic angiography with intent to perform revascularization) is not recommended in patients with extensive comorbidities such that the risks of revascularization are likely to outweigh the benefits of revascularization, or in patients with acute chest pain and a low likelihood of ACS (class III recommendation) (Figure 31-11).⁵⁹

Both aspirin and thienopyridines have been shown to improve outcome in patients with ACS. As soon as there is a suspicion of ACS, 162 to 325 mg of a nonenteric formulation of aspirin should be given orally or chewed unless there is a contraindication.

The thienopyridines (ticlopidine, clopidogrel, and prasugrel) and ticagrelor, a cyclopentyl triazolo-pyrimidine, block the P2Y₁₂ adenosine diphosphate receptor on platelets. Clopidogrel requires in vivo biotransformation to an active metabolite. The active metabolite irreversibly blocks the P2Y₁₂ component of adenosine diphosphate receptors on the platelet surface, which prevents activation of the GpIIb-IIIa receptor complex and reduces platelet aggregation for the remainder of the platelet's life span, which is approximately 7 to 10 days. Prasugrel is a prodrug that is metabolized to both active and inactive metabolites. Platelet aggregation returns to baseline within 5 to 9 days after prasugrel is discontinued.

The efficacy of clopidogrel was studied in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial, which randomized 12,562 patients with UA/NSTEMI to either clopidogrel (300-mg oral loading dose, then 75 mg daily) or placebo for a mean of 9 months; all patients also received aspirin (dose range, 75-325 mg).¹³⁶ The primary end point was cardiovascular death, MI, or urgent target-vessel revascularization at 30 days after PCI. The incidence of the 30-day composite end point was significantly lower among patients who received clopidogrel (4.5%) than among patients who received placebo (6.4%). The PCI-CURE trial studied a subset of patients (n = 2658) who underwent PCI.¹³⁷ Overall, including events before and after PCI, there was a 31% reduction in cardiovascular death or MI (P < .002). There was no difference between the groups in major bleeding.¹³⁷ Therefore, in patients with UA/NSTEMI who undergo PCI, pretreatment with clopidogrel followed by up to 1 year of clopidogrel therapy is beneficial in reducing major cardiovascular events. However, PCI-CURE did not adequately address the question of dose or timing of clopidogrel in relationship to PCI. The CREDO trial randomized 2116 patients to a 300-mg loading dose of clopidogrel or placebo (3-24 hours before PCI). Both groups received 325 mg of aspirin. The clopidogrel group received 75 mg of clopidogrel daily for 1 year. Although there was no difference between groups in the 28-day composite end point of death, MI, and urgent target-vessel revascularization, treatment with clopidogrel was associated with a 26.9% relative risk reduction in the 1-year composite end point of death, MI, and stroke.¹³⁸

Prasugrel, a new thienopyridine, was compared with clopidogrel in a randomized, double-blind trial, TRITON-TIMI 38. It compared prasugrel (loading dose of 60 mg followed by maintenance dose of 10 mg) with clopidogrel (300-mg loading dose followed by 75-mg maintenance dose) in 13,608 patients with UA/NSTEMI (n = 10,074) or STEMI (n = 3534) who underwent PCI. All patients also received aspirin, and treatment with prasugrel or clopidogrel was continued for a median of 14.5 months. The primary end point, a composite of cardiovascular death, nonfatal MI, and nonfatal stroke, was less frequent among patients who received prasugrel (9.9% versus 12.1%; hazard ratio: 0.81; 95% CI: 0.73-0.90). The rate of major bleeding was higher in the prasugrel group (2.4% versus 1.8%; hazard ratio: 1.32; 95% CI: 1.03-1.68), as was the rate of life-threatening bleeding.¹³⁹

Ticagrelor, which reversibly binds to the P2Y₁₂ platelet receptor and has not been approved for clinical use, exhibited greater efficacy than clopidogrel in the PLATO trial. Major bleeding events did not differ between the groups, although bleeding not related to coronary artery bypass grafting occurred more often with ticagrelor.¹⁴⁰ Both prasugrel and ticagrelor may have a quicker onset of action than clopidogrel and may prove to be very useful in patients who are clopidogrel-resistant. The current guidelines recommend a loading dose of 300 to 600 mg of clopidogrel in patients with UA/NSTEMI followed by 75 mg daily.⁵⁹ The duration of clopidogrel use may depend on whether or not the patient received a stent. Ideally, clopidogrel should be continued indefinitely if it is tolerated by the patient. However, adequate long-term data have not been sufficient to formulate a definite recommendation on the duration of therapy.

The efficacy of unfractionated heparin, low-molecular-weight heparins, fondaparinux, bivalirudin, and GpIIb-IIIa inhibitors has been extensively studied in patients with ACS. A discussion of the numerous trials is beyond the scope of this chapter. In the new era of clopidogrel use, the utility of GpIIb-IIIa inhibitors has been questioned. The current evidence base and expert opinion suggest that for patients with UA/NSTEMI in whom an initial invasive strategy is selected, either an intravenous GpIIb-IIIa inhibitor or clopidogrel should be added to acetylsalicylic acid (ASA) and anticoagulant therapy before diagnostic angiography for lower-risk, troponin-negative patients. In higher-risk and troponin-positive patients, both clopidogrel and a GpIIb-IIIa inhibitor should be started before angiography (class I recommendation).⁵⁹ For patients with UA/NSTEMI in whom an initial conservative strategy is selected, the addition of a GpIIb-IIIa inhibitor to anticoagulant and oral antiplatelet therapy may be reasonable for high-risk patients (class IIb recommendation).⁵⁹ Recommendations for antiplatelet and anticoagulant therapy are listed in Tables 31-11, 31-12, and 31-13.

Cocaine-induced ischemic chest pain is often clinically indistinguishable from UA or NSTEMI. Cocaine-induced coronary artery vasoconstriction has been demonstrated in both in vivo^{141, 142, 143, 144, 145} and in vitro experiments.¹⁴⁶ In addition to its direct effect on vasomotor tone, cocaine promotes coronary thrombosis by increasing the response of platelets to arachidonic acid, thus increasing thromboxane A₂ production and platelet aggregation.¹⁴⁷ Chronic use of cocaine may promote accelerated atherosclerosis. Therefore, patients using cocaine who present with ischemic-like chest discomfort should be treated aggressively. If the initial ECG shows ST-segment elevation or depression, intravenous or sublingual nitroglycerin or an intravenous calcium channel blocker (such as diltiazem) should be administered immediately. If there is no improvement in the ECG, then fibrinolytic therapy or PCI should be considered after consultation with a cardiologist. If the initial ECG is nondiagnostic for ischemia, then nitroglycerin or a calcium channel blocker should be administered and the patient should be monitored for a minimum of 24 hours with serial ECGs and cardiac biomarkers as well as continuous ECG monitoring.⁵⁹ The use of β blockers in patients with cocaine-related chest discomfort remains controversial. Current recommendations support the use of calcium channel antagonists (diltiazem or verap-amil) over β blockers in this setting.

This patient is experiencing variant or Prinzmetal angina. The exact mechanism for CAS in variant angina is unknown but may be due to increased vasomotor tone, vagal withdrawal, abnormal sympathetic activity, or endothelial dysfunction. Patients with either obstructive or nonobstructive coronary artery disease can have CAS.¹⁴⁸ Patients may have typical angina or be asymptomatic. Compared to patients with UA/NSTEMI, patients with variant angina are younger and have little or no cardiac risk factors. The attacks of angina usually resolve spontaneously without evidence of MI. However, a prolonged episode of vasospasm may result in complications such as MI, high-grade AV block, life-threatening ventricular tachycardia, or sudden death.^{149, 150}

The key to diagnosing variant angina due to CAS is recording transient ST-segment elevation that resolves when the chest pain resolves or after administration of nitroglycerin. Nitrates and calcium channel antagonists are the first line of therapy for CAS. Moderate to high doses of a calcium channel blocker should be prescribed (eg, verapamil 240-480 mg daily, diltiazem 180-360 mg daily, or nifed-ipine 60-120 mg daily). The addition of nitrates and/or a second calcium channel antagonist may be necessary if the CAS is severe and recurrent. Coronary angiography is recommended in patients with episodic chest pain accompanied by transient ST-segment elevation (class I recommendation).⁵⁹

Overall, patients with variant angina due to CAS have an excellent prognosis with medical management. Occasionally, patients may need a permanent pacemaker to prevent transient AV block associated with ischemia during periods of prolonged coronary vasospasm. In this patient's case, the recurrent syncope should alert the clinician to ischemia-induced AV block or ventricular fibrillation during prolonged episodes of CAS, which may require a pacemaker or defibrillator.

This patient's initial ECG shows diffuse T-wave inversions with a T-wave morphology that is suggestive of ischemia. Furthermore, the initial laboratory results are indicative of myocardial necrosis with a serum troponin level of 1.33 ng/mL. Despite having no identifiable cardiac risk factors, the patient's chest pain, ECG results, and increased troponin levels are consistent with NSTEMI. The fact that the T-wave inversions are diffuse rather than regional does not rule out ACS. Until further data can be collected, it is reasonable to treat this patient as if she is having an NSTEMI. Aspirin, clopidogrel, and anticoagulation should be initiated according to the UA/NSTEMI guidelines that were discussed earlier. Other medications such as β blockers should be started if appropriate. Given her lack of cardiac risk factors and onset of chest pain after extreme emotional stress (ie, diagnosis of a brain mass), one should suspect a stress-induced cardiomyopathy, also known as apical ballooning syndrome, broken heart syndrome, or Takotsubo cardiomyopathy.

The differential diagnosis includes NSTEMI, coronary vasospasm, myocarditis, left ventricular hypertrophy, central nervous system disease, and pericarditis (stage III of ECG findings).

Coronary angiography should be performed to detect epicardial coronary artery occlusion. Left ventriculography will reveal akinesis of the left ventricular apex and/or the midportions of the left ventricle and a hypercontractile base. A 2-D echocardiogram would confirm these findings. Severe left ventricular dysfunction is common.

Generally, the diagnosis of stress-induced cardiomyopathy can be made if all four of the following criteria are met: (1) an ECG shows ST-segment elevation or T-wave inversions, or positive cardiac biomarkers; (2) there is no angiographic evidence of coronary artery occlusion; (3) an echocardiogram shows transient hypokinesis, akinesis, or dyskinesis of the left ventricular wall from the midportion to the apex, with hypercontractility of the base; and (4) other diseases such as myocarditis have been excluded.^{151, 152}

Stress-induced cardiomyopathy typically occurs in postmenopausal women, presents with chest pain and dyspnea, and is associated with emotional distress or critical illness. A systematic review performed in 2006 reported chest pain and dyspnea in 67.8% and 17.8% of the patients, respectively.¹⁵³ ECG changes included ST-segment elevation in 81.6% of the patients, T-wave abnormalities in 64.3%, and Q waves in 31.8%.¹⁵³ Cardiac biomarkers were usually mildly elevated, as reported in 86.2% of the patients.¹⁵³ The pathogenesis of stress-induced cardiomyopathy is unclear. Multivessel coronary vasospasm has been postulated but not proven. Other possible mechanisms include catecholamine excess.

Stress-induced cardiomyopathy is transient and initially requires supportive care. A proportion of patients can present with decompensated heart failure, cardiogenic shock, or lethal ventricular arrhythmias. In one study, the incidence of cardiogenic shock and ventricular fibrillation was reported to be 4.2% and 1.5%, respectively.¹⁵³

Therapy for heart failure is indicated until recovery of LV function has been demonstrated by 2-D echocardiography. Recovery time varies but is usually 1 to 4 weeks. There is no official recommendation on the duration of therapy, but it should at least continue until LV systolic function has returned to normal on imaging studies. Prognosis is generally good despite the fact that many patients are critically ill at the onset of stress-induced cardiomyopathy. In-hospital mortality rates range between 0% and 8%.^{151, 154, 155, 156} Recurrence rates are unclear but were reported to be 3.5% in one study.¹⁵³

There are several mechanical complications that can occur after acute MI and that are often life threatening if not diagnosed and treated promptly. In addition to providing supportive care with vasopressor and/or vasoactive drugs, the first step in diagnosing this patient's worsening hemodynamic status is a 2-D echocardiogram. Two-dimensional echocardiography is crucial in diagnosing mechanical complications of acute MI, such as acute mitral regurgitation due to papillary muscle rupture, rupture of the interventricular septum, rupture of the left ventricular free wall, or cardiac tamponade.

Ischemic MR frequently occurs in the setting of acute MI due to ischemic papillary muscle displacement, left ventricular dilatation of an aneurysm, or rupture of a papillary muscle or chordae. Transient moderate MR can occur in up to 14% of patients with acute MI during periods of ischemia.¹⁵⁷ One study showed that mild MR (8.5% mortality rate) and moderate to severe MR (20.8% mortality rate) in the setting of acute MI were the strongest independent predictors of 1-year mortality.¹⁵⁸ The diagnosis of severe acute MR should be suspected in any patient after acute MI who develops hypotension and pulmonary edema. The absence of a loud systolic murmur does not exclude severe MR. Treatment of acute severe MR includes inotropic support, afterload reduction, an intra-aortic balloon pump, and emergency mitral valve surgery. Despite these treatments, mortality rate remains high.

Ventricular Septal Rupture

Prior to the use of reperfusion therapy, ventricular septal rupture occurred in approximately 2% of acute infarctions and probably accounted for 10% of cardiac ruptures.¹⁵⁹ However, the incidence of ventricular septal rupture was only 0.2% among patients who received fibrinolytic therapy in the GUSTO-1 trial. Sixty-seven percent of the patients with ventricular septal rupture in the GUSTO-1 trial developed cardiogenic shock. The mean time from onset of MI to ventricular septal rupture was approximately 1 day.¹⁶⁰ Septal rupture is seen with equal frequency in anterior and nonanterior infarctions. Clinical manifestations include chest pain, hypotension, dyspnea, and a harsh holosystolic murmur. The diagnosis is made by 2-D echocardiography with color Doppler imaging and/or insertion of a pulmonary artery balloon catheter to document a left-to-right shunt. Vasodilators, inotropic agents, and an intra-aortic balloon pump are used to initially stabilize the patient, but surgical repair portends the greatest survival benefit. In the GUSTO-1 trial surgical repair was performed at a median of 3.5 days after the onset of MI. Patients selected for surgery had better outcomes than patients treated medically (n = 35; 30-day mortality rate, 47% versus 94%).¹⁶⁰ However, it might be reasonable to delay surgery in patients who are hemodynamically stable without evidence of cardiogenic shock.

Left Ventricular Free Wall Rupture

Rupture of the left ventricular free wall may manifest in any of several ways: pericardial tamponade with acute hemodynamic collapse and immediate death, gradual onset of tamponade and hypotension, or subacute formation of a pseudoaneurysm with recurrent chest discomfort.¹⁶¹ Risk factors for LV free wall myocardial rupture include anterior location of the infarction, a large transmural MI, absence of collateral blood flow, age older than 70 years, and female gender.^{162, 163} Rupture usually occurs between 5 days and 2 weeks after acute MI, and most often occurs in the anterior or lateral LV wall at the junction between normal and infarcted myocardium. The incidence of rupture among a series of 1378 patients was 3.3% among patients treated with fibrinolytic therapy and 1.8% among patients treated with PCI.¹⁶³ The goal of therapy is to stabilize the patient with fluids, inotropic support, vasopressors, pericardiocentesis, and an intra-aortic balloon pump until surgical repair is feasible.

ECG changes in the acute phase of subarachnoid hemorrhage (SAH), cerebral infarction, and intra- cerebral hemorrhage have been reported. Abnormal ECG findings include ST-segment elevation and depression, T-wave inversions and flattening, repolarization abnormalities, and QT prolongation. ECG changes that appear ischemic such as ST-segment depressions or T-wave inversions can occur in patients with and without underlying coronary artery disease. A systematic review of ECG changes in patients with acute stroke published in 2002 reviewed 29 observational, experimental, prospective, and retrospective studies. The studies were extremely heterogeneous. Patient populations were categorized as having “known heart disease” and “no known heart disease,” terms that were loosely defined across studies. Details regarding ECG interpretation were vague. However, the incidence of ST-segment elevation in patients with SAH and no known heart disease was 31%; 35% had ST-segment depression, 19% had T-wave inversions, 27% had unspecified ST-segment or T-wave changes, and 4% had pathologic Q waves. There were very limited data regarding ECG changes in patients with ICH, cerebral infarction, or transient ischemic attack.¹⁶⁴ A descriptive study that confirmed SAH by CT scan found that 55% of patients had either T-wave inversions or T-wave flattening, despite no detectable cardiac abnormalities at autopsy.¹⁶⁵ When interpreting ECG changes in acute stroke patients, age, cardiac history, and ancillary data such as cardiac biomarkers are crucial in distinguishing a true ischemic event from neurogenic-mediated cardiac damage.

Very few studies have reported on this possible correlation. One small prospective study published in 2004 followed 162 patients (mean age: 62.4 ± 14 years) for 4 weeks after a first ischemic stroke was confirmed by CT.¹⁶⁶ A detailed medical history and clinical information were obtained from each patient. During the 4-week follow-up period, 44 of 162 patients died. Clinical characteristics and ECG changes were compared in survivors and nonsurvivors. Patients were excluded if they had any signs or symptoms of coronary artery disease; use of cardiac drugs; cerebral infarction due to cardiac embolism, SAH, or ICH; cerebral tumors; left ventricular hypertrophy; or left bundle branch block or right bundle branch block on ECG. ECGs were interpreted by a cardiologist who was blinded to the study. Sixty-five percent of all patients had ischemic-like ECG changes. Survivors had a significantly lower frequency of ischemic-like ECG changes when compared with nonsurvivors (60% versus 77%; P = .044). Thirty-three percent of survivors and 61% of nonsurvivors had ST-segment depression or ST-segment elevation (P = .001). By univariate analysis, predictors of early mortality were advanced age (P = .01), presence of ST-segment changes (P = .001), and abnormal U waves (P = .03). Multivariate analysis showed that age older than 65 years and presence of ST-segment changes were the only significant predictors for early mortality.¹⁶⁶ Although these data suggest that ischemic-like ECG changes are independent predictors of mortality, the results are difficult to interpret because no effort was made to diagnose asymptomatic coronary artery disease. Interestingly, 33% of patients had atrial fibrillation (AF), but the presence of AF had no predictive value for mortality. Previous studies have shown that AF and conduction defects are associated with threefold and fivefold increases in mortality in patients with cerebrovascular events.¹⁶⁷

Christensen et al studied the admission ECGs of 1070 patients with cerebral infarction (n = 692), ICH (n = 155), or transient ischemic attack (n = 223) and followed them for 3 months. In multivariate analyses, 3-month mortality in patients with ischemic stroke was predicted by atrial fibrillation (OR: 2.0; 95% CI: 1.3-3.1), atrioventricular block (OR: 1.9; 95% CI: 1.2-3.9), ST-segment elevation (OR: 2.8; 95% CI: 1.3-6.3), ST-segment depression (OR: 2.5; 95% CI: 1.5-4.3), and inverted T waves (OR: 2.7; 95% CI: 1.6-4.6). These findings were independent of age or stroke severity.¹⁶⁸