Chapter 124. Acute Coronary Syndromes

1. What are the available tools to diagnose and risk stratify patients with suspected acute coronary syndrome (ACS)?

2. What are the American College of Cardiology and American Heart Association (ACC/AHA) class I guideline recommendations for anti-ischemia and antithrombotic therapy for unstable angina (UA) and non-ST-elevation myocardial infarction (NSTEMI)? For STEMI? Which drugs reduce mortality?

3. What are the benefits of an invasive versus a conservative strategy for managing UA/NSTEMI?

4. Which patients should undergo early invasive therapy in the setting of ACS?

The term acute coronary syndrome (ACS) refers to a group of clinical symptoms consistent with acute myocardial ischemia, whether from unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or ST-segment elevation myocardial infarction (STEMI). The definition of STEMI is based on the electrocardiographic (ECG) criteria of ST-segment elevation, and this diagnosis accounts for 330,000 hospital admissions per year in the United Sstates. The definition of NSTEMI is based on the absence of ST-segment elevations on the ECG, but ST depression and T-wave inversions may be evident, and there is sufficient ischemic damage to cause biochemical evidence of myonecrosis. NSTEMI accounts for 570,000 hospital admissions per year. UA and NSTEMI have similar pathogenesis and clinical presentations, but UA is not associated with release of cardiac troponins and/or creatine kinase (CK-MB). UA accounts for 670,000 admissions per year. According to the American Heart Association (AHA), an estimated $177 billion has been spent on the treatment of coronary heart disease in 2010.

Although tremendous strides have been made in the management of cardiovascular disease, coronary heart disease currently accounts for almost 20% of deaths in the United States. The 30-day mortality associated with the diagnosis of ACS varies from 1.7% for patients with UA to 7.4% for patients with NSTEMI to 11.1% for those with STEMI.

Despite chest pain pathways to guide clinicians in risk stratification, approximately 5% of symptomatic patients with myocardial infarction are inappropriately discharged from the emergency department to the outpatient setting. In addition, nearly 50% of all myocardial infarctions (MIs) produce no symptoms.

This chapter will focus on patients diagnosed with ACS, encompassing STEMI, NSTEMI, and UA, and review the best medical evidence based on the latest pertinent clinical trials reporting diagnosis and management of ACS. Recommendations will be referenced according to the American College of Cardiology (ACC)/AHA guidelines for the management of patients with STEMI and UA/NSTEMI along with the 2007 focused update of these guidelines. This chapter will not review the rapid rule-out protocols for the more than 75% of 5 million patients who present to emergency departments in the United States annually and have no evidence of ACS. Noncardiac chest pain and chronic stable angina are covered elsewhere in this book (Specific treatments/interventions may be described in relation to ACC/AHA guideline recommendations as per the class scheme explained in Table 124-1).

The key event in the vast majority of ACS presentations concerns the abrupt disruption of a preexisting fibrous plaque involving primarily the intima of large- and medium-sized coronary arteries. Coronary artery thrombosis may result from complete plaque rupture, superficial plaque erosion, or a calcified plaque nodule. The exact mechanisms whereby a previously stable plaque is rendered “unstable” are not fully understood, but a key role for inflammatory cells has been advanced in the development of thin-cap fibroatheroma located predominantly in the proximal and mid sections of the three major coronary arteries and, importantly, within areas of <50% arterial stenosis. Accurately predicting vulnerable plaques in the clinical setting is difficult because plaque composition rather than size affects both the likelihood of rupture and the exposure of prothrombotic material such as cholesterol, collagen, and fibrin to platelets, and coagulation cascade elements to the endothelium.

Transmural ischemia from occlusion of a coronary thrombus causes STEMI; whereas nonoccluding thrombus leads to UA or NSTEMI (Figure 124-1).

UA and NSTEMI often arise from a combination of potential mechanisms, including the following:

1. Decreased blood delivery to the downstream myocardium, often due to a partially occlusive thrombus overlying a disrupted atherosclerotic plaque, from microembolization of thrombus and plaque debris with resulting blockage of the distal microcirculation

2. Fixed severe narrowing caused by progressive atherosclerosis or in-stent restenosis resulting in sufficient collateral blood flow around the stenosis to prevent transmural infarction when a fully occlusive thrombosis occurs

3. Dynamic obstruction caused by intense vasospasm, often referred to as Printzmetal angina, cocaine-induced vasoconstriction, or other causes of vasoconstriction

4. Inflammatory or infectious initiators of arterial narrowing, plaque rupture, and/or thrombogenesis

5. Increased myocardial oxygen demand (fever, tachycardia, hyperthyroidism, and other hyperadrenergic states, elevations of left ventricular afterload from hypertension, severe aortic stenosis, hypertrophic cardiomyopathy) and reduced myocardial oxygen delivery (anemia, hypoxemia, hypotension) despite normal coronary arteries

Spontaneous coronary artery dissection is a rare cause of ACS and is often linked with hormonal imbalance in connection with pregnancy, connective tissue disorders such as Marfan and Ehlers-Danlos syndromes, or with thoracic aortic dissection.

The 2007 ACC/AHA guidelines for managing UA and NSTEMI recommend that practitioners use the patient's history, physical examination, ECG interpretation, and results of cardiac biomarkers to determine the likelihood that the patient's presentation is ACS from obstructive coronary artery disease (CAD). The diagnosis for STEMI is made on the basis of ST-segment elevation in the appropriate clinical setting.

History

Classic ACS-associated symptoms include chest, upper limb extremity, and jaw or epigastric pain or discomfort at rest or associated with exertion or emotional stress. In general, diffuse, nonpositional, poorly localized chest pain or discomfort is present in three-quarters of patients presenting with acute MI. Patients may also describe upper abdominal pain or associated symptoms such as shortness of breath, diaphoresis, nausea, and presyncope or syncope. Symptoms persisting for more than 20 minutes suggest infarction rather than UA. Diabetic patients or other patients with autonomic neuropathy, women and elderly patients, and postoperative patients may not exhibit the classic symptoms of ACS. They may present with hypotension that is unexplained, pulmonary edema, delirium, or profound weakness. Vigorous physical exercise such as shovelling snow, intense emotion such as arguing with a family member, and medical or surgical stress may precipitate STEMI in as many as 50% of cases. Circadian variations may be a factor in clusters of cases within a few hours of awakening.

The Braunwald classification system for UA hinges on the assessment of severity of the patient's anginal symptoms (I. new-onset of severe angina or increasing angina not occurring at rest; II. angina at rest in the past month but not in the preceding 48 hours, III. rest angina within the past 48 hours), the clinical setting (A. unstable angina secondary to a non-cardiac condition that increases demand, B. primary unstable angina, and C. postinfarction angina within 14 days of acute MI), and presence or absence of accompanying transient ECG changes. Table 124-2 lists the Canadian Classification.

Although traditional cardiac risk factors are weak predictors of the likelihood of acute ischemia, their presence influences outcomes in patients diagnosed with ACS. For example, diabetic patients with UA/NSTEMI have a 50% greater risk of adverse cardiac outcomes than nondiabetic patients. Well-documented risk factors for obstructive CAD include age > 65, hypertension, hypercholesterolemia, diabetes, and tobacco exposure, and family history of CAD especially in a sibling. The examiner should also determine risk factors for other causes of life-threatening chest pain that would alter any management strategy using antithrombotic and antiplatelet agents. (See Chapter 77 for a more detailed discussion of chest pain.) Acute aortic dissection, pulmonary embolism, esophageal rupture, tension pneumothorax and cardiac tamponade may mimic the signs and symptoms of acute MI (Table 124-3).

Physical Examination

Although most patients with chest pain will have an unrevealing physical examination, the examiner should first look for signs of cardiac compromise that may signify a large infarction and poor prognosis. Anterior MI may be associated with hypotension and tachycardia in approximately 25% of cases, whereas inferior MI may be associated with bradycardia and hypotension in up to 50% of cases. Low cardiac output may be suggested by the presence of low blood pressure, significantly reduced mean arterial pressure compared to the patient's baseline, and sinus tachycardia accompanied by diaphoresis, pale cool skin, confusion, and reduced urine output. Signs of elevated filling pressures include a palpable or audible S3, audible S4, elevated jugular venous distention, or rales. A midsystolic or late-systolic apical murmur may result from mitral valve dysfunction. Right ventricular infarction may have signs of hypotension (eg, elevated jugular venous distention) without signs of left ventricular failure. A transmural MI may produce a transient pericardial friction rub. The examiner should also look for signs of precipitating factors (eg, severe hypertension, hyperthyroidism, hemorrhage or other causes of severe anemia, and hypoxia) and for signs of vascular disease.

ECG

ECG interpretation facilitates making the diagnosis of ACS and stratifying risk. Despite limitations of the ECG in signifying ischemia of the posterior, lateral, and apical walls of the left ventricle, the admission ECG strongly predicts both early and long-term prognosis. Although a normal ECG on admission may be associated with as high as a 10% incidence of NSTEMI, and an acute MI resulting from left circumflex artery occlusion may be missed in at least 4% of cases, patients with no ECG findings have a lower risk of complications than those with new ECG abnormalities. ST deviation of only 0.5 mm (0.05 mV) increases the 30-day and 1-year risk of mortality or MI twofold.

The ACC/AHA guidelines recommend obtaining an ECG within 5 minutes of acute chest pain presentation so that it can be interpreted by an experienced physician within 10 minutes of arrival.

The patient should be placed on a cardiac monitor in immediate reach of resuscitation equipment including a cardiac defibrillator. Patients should have a bedside chest plain film that screens for alternative diagnoses and for pulmonary congestion (associated with an adverse prognosis). A bedside two-dimensional echocardiograph will detect abnormalities of wall motion in all cases of STEMI and, thus, may be indicated when there is uncertainty about the diagnosis (eg, pericardial effusion, RV infarction, ventricular aneurysm, or LV thrombus), the need for emergent reperfusion therapy, or prognosis (eg, reduced left ventricular function).

Is This Patient Experiencing a STEMI?

If the patient is experiencing a STEMI, a decision with regard to reperfusion strategy should be made as quickly as possible (within 10 minutes of arrival to the health care facility). ST-segment elevation of 1 mm (0.1 mV) or more in two or more contiguous leads or new left bundle-branch block (LBBB) is highly indicative of acute MI in 90% of patients. Sgarbossa's criteria refers to the ECG criteria for identifying acute MI in patients with LBBB or ventricular pacing: (1) ST-segment elevation of ≥ 5 mm in the presence of a negative QR complex, (2) ST-segment elevation of ≥ 1 mm in the presence of a positive QRS complex, and (3) ST-segment depression of ≥ 1 mm in lead V1, V2, or V3. Additional ECGs encompassing right ventricular and posterior leads should be performed if inferior or posterior MI is suspected. ST-segment depression in two contiguous anterior precordial leads and/or lone ST-segment elevation in the posterior chest leads signify a true acute posterior MI. Right ventricular infarction accompanies inferior-posterior wall MI in 30% to 50% of patients. The diagnosis is made on the basis of ST-segment deviation of ≥ 1 mm (0.1 mV) in the right precordial lead V4R. Recognition is important due to the need for volume expansion, the possibility of advanced atrioventricular nodal block, and worse prognosis relative to patients suffering from interior-posterior MI without RV infarction. ECG interpretation is needed for identification of infarct territory in acute myocardial infarction (AMI) and to differentiate common nonischemic causes of ST-segment elevation including early repolarization, acute pericarditis, pulmonary embolism, left ventricular hypertrophy, Brugada syndrome, and others. (See Chapter 102 for a detailed discussion of electrocardiographic interpretation.)

Is This Patient Experiencing UA or an NSTEMI?

Patients with ST-segment depression, transient ST-segment elevation, or deep symmetrical T-wave inversion (> 2 mV) are initially diagnosed with ACS until cardiac biomarkers distinguish between UA and NSTEMI. Lesser degrees of ST-segment deviation (< 0.5 mV) and/or T-wave changes are less specific, but the more leads that have these “nonspecific” changes, the greater is the likelihood of an acute NSTEMI rather than UA.

The ACC/AHA guidelines recommend serial ECG tracings or continuous ST-segment monitoring for patients with UA and NSTEMI.

Cardiac Biomarkers

Measurement of the cardiac troponins (T or I), may provide confirmatory evidence of myocardial necrosis within two to three hours in 80% of patients with acute MI. Current guidelines advocate repeated cardiac troponin (cTn) measurements at 6 and 12 hours post symptom onset to exclude MI. The biomarker of choice, cTn elevation, almost always reflects myocardial necrosis and has proved to be a powerful predictor of mortality in those with ACS. False positives may arise due to cross-reacting antibodies or as a consequence of fibrin interference. Between 15% and 53% of patients with end-sage renal disease (ESRD) may have positive cTnT measurements in the absence of myocardial necrosis compared with 10% for cTnI. However, all elevations of cTn, even in those patients without demonstrable myocardial necrosis, such as those with falsely elevated cTnT in the setting of severe renal dysfunction, are associated with increased morbidity.

CK-MB remains part of a multi-marker test to diagnose early MI and continues to be very useful in the diagnosis of re-infarction or infarct extension or peri-procedural MI due to its shorter half-life. Commonly, CK-MB levels are relied upon to estimate infarct size despite evidence to suggest that cTn (at 72–96 hours) may reflect the extent of myocardial necrosis with greater accuracy.

The 2007 ACC/AHA guidelines for ACS recommend early stratification for risk of short-term death or nonfatal MI to determine the site of care, specific therapy, approach (early invasive versus conservative strategy), and prognosis. Treatment of possible, probable, or definite ACS should occur in a chest pain unit (CPU), medical telemetry unit, or coronary care unit (CCU) depending on the level of suspicion or confirmation of ACS. Low-risk patients can be evaluated in a CPU or medical telemetry unit. Patients with evidence of STEMI or other significant ECG changes, as well as those with any hemodynamic instability or new arrhythmia, should be evaluated in the CCU setting.

Treatment goals depend on the underlying pathophysiology. In STEMI, the initial approach involves immediate pharmacologic or catheter-based reperfusion to obtain normal coronary blood flow in a previously totally occluded artery. Time is critical for initial perfusion therapy: the golden hour is the first 60 minutes after presentation, and total ischemic time should be less than 90 to 120 minutes. The majority of patients will receive concomitant treatments with proven efficacy. In unstable angina and NSTEMI, the goal is to identify and remedy secondary causes that may increase myocardial oxygen demand or impair myocardial oxygen delivery, provide antithrombotic therapy to prevent further thrombosis and allow endogenous fibrinolysis to dissolve the thrombus, and employ revascularization to increase blood flow and prevent reocclusion. Although reperfusion therapy improves outcomes for STEMI, fibrinolysis has no role in the management of either UA or NSTEMI ACS. A meta-analysis not only showed no benefit in this setting, but showed an increased rate of MI. Therefore, treatment hinges on distinguishing between STEMI and UA/NSTEMI and then identifying high-risk patients with UA/NSTEMI who may benefit from invasive evaluation. The goal of secondary prevention for all patients is to stabilize and halt the progression of atherosclerotic plaques.

The key question to ask is whether the patient is having a STEMI. A broad array of management strategies for STEMI requires emergent cardiology consultation and possible expedited interhospital transfer. Reperfusion therapy has the advantages of being widely available and quick to administer; percutaneous coronary intervention (PCI) is more effective and has a lower bleeding risk but has limited availability and may cause treatment delays (Figure 124-2).

If initial testing suggests that the patient is having a NSTEMI, it is then incumbent on the practitioner to identify high-risk clinical subgroups to guide clinical decision making in order to salvage as much myocardium as possible. The clinical spectrum of non-ST-segment elevation ACS ranges from low-risk patients who would not benefit from early angiography with PCI or a selectively invasive strategy to intermediate and high-risk patients who would likely benefit due to a higher likelihood of adverse cardiac events.

Treatment of STEMI

All patients with STEMI should receive dual therapy with aspirin and clopidogrel regardless of whether they undergo reperfusion with fibrinolytic therapy or do not receive reperfusion (class Ia). In patients for whom coronary artery bypass graft (CABG) surgery is planned, clopidogrel should be held at least five days, preferably seven days, unless the urgency for revascularization outweighs the risk of increased bleeding (class I). In patients less than 75 years of age, it is reasonable to administer a loading dose of clopidogrel 300 mg (class IIa); no data are available to support loading in older patients. Long-term maintenance of one year may be reasonable for patients with STEMI regardless of whether they underwent reperfusion therapy (class IIa).

Morphine for pain control remains a class I recommendation for STEMI, although it may increase adverse events in NSTEMI.

What Is the Optimal Reperfusion Strategy for This Patient with STEMI?

Following recognition and diagnosis of an acute STEMI, a rapid decision with regard to reperfusion eligibility (whether fibrinolysis or PCI) and strategy must be made by the physician.

Ongoing treatment should then be carried out in the coronary care setting. The current ACC/AHA guidelines stipulate that all hospitals performing primary PCI should achieve a median door-to-balloon time of less than 90 minutes, with at least 75% of patients treated reaching this 90-minute target from first medical contact. If these time constraints cannot be met, fibrinolysis should be administered unless contraindicated.

The European Society of Cardiology (ESC) guidelines extend the 90-minute timeframe from first medical contact to PCI to 120 minutes. Furthermore, patients who present late with STEMI (> 12 hours) and who are hemodynamically stable should be transferred for PCI rather than receive thrombolysis. High-risk patients (elderly, those with anterior MI, renal impairment, or LV dysfunction) appear to sustain higher mortality rates undergoing primary PCI when a PCI-related delay is encountered.

When performed at a high-volume center (> 200 PCI procedures yearly) by experienced and skilled operators (> 75 PCI per year), primary PCI is the superior treatment modality for STEMI. Primary PCI leads to higher infarct-related artery (IRA) patency compared to fibrinolytic therapy alone. Primary PCI as opposed to thrombolysis has been shown to prevent 2 deaths per 100 patients treated (NNT = 50). Sicker STEMI patients appear to derive most benefit from PCI. Furthermore, primary PCI is associated with a lower risk of hemorrhagic stroke (0.05% versus 1.1%).

One of the major limitations to primary PCI therapy in the setting of an acute STEMI is achieving rapid transfer and access to a PCI-equipped center. It is estimated that less than one-quarter of acute care hospitals in the U.S. have PCI capabilities, though approximately 80% of the population reside within one hour of facilities with such capabilities. As the extent of myocardial necrosis and clinical outcomes are intrinsically linked to the duration of occlusion of the infarct-related artery, the point at which the delay in initiating PCI negates the advantages of prompt fibrinolysis is hotly debated. Primary PCI in a center without cardiac surgery availability is given a class IIb recommendation in 2007 ACC/AHA guidelines, although considerable data exist demonstrating excellent results compared with those facilities that have on-site cardiothoracic surgery.

Pharmacologic reperfusion is indicated in those circumstances where ECG criteria are met and symptom onset is < 12 hours (class IA) where prompt access to PCI is not possible, and no contraindications exist. Patients with a posterior STEMI presenting within 12 hours of symptom onset with no contraindications to fibrinolysis should also receive pharmacologic reperfusion (class IIA level of evidence C). Those STEMI patients who present 12 to 24 hours after symptom onset, who meet ECG criteria with recurrent ischemic symptoms also are given a class IIA recommendation for fibrinolytic therapy.

The U.S. Food and Drug Administration has approved tissue plasminogen activator (tPA), streptokinase, tenecteplase (TNK), and reteplase (rPA) as fibrinolytic agents, all of which promote the conversion of plasminogen to plasmin. Patients treated within one to three hours of the onset of symptoms clearly benefit the most regarding reduction of infarct size, limiting LV dysfunction, septal rupture, cardiogenic shock, ventricular arrhythmias, and death. Unlike streptokinase, newer fibrinolytic agents do not provoke an immune response and have been shown to result in greater infarct-related artery patency rates and a lower 30-day mortality benefit (Table 124-4).

Patients receiving fibrinolysis should be treated with dual antiplatelet therapy in addition to anticoagulation. 2007 ACC/AHA guidelines recommend that anticoagulation (unfractionated heparin [UFH], enoxaparin, or fondaparinux) should be continued for a minimum of 48 hours and up to eight days unless contraindicated. The TIMI risk score for STEMI enables the physician to rapidly assess the patient's 30-day mortality based on history and clinical exam, and ECG. Importantly, delay in treatment is associated with a higher mortality. Of 14 possible points, if the risk score is greater than 8 points, the associated mortality is 35.9% at 30 days.

When Should an Invasive Strategy Be Considered Post Fibrinolysis for STEMI?

The timing of when to refer for PCI appears crucial in relation to maximizing potential benefits of restoring infarct-related artery (IRA) myocardial blood flow while minimizing major bleeding risks attendant with recent fibrinolysis. The process whereby a patient with acute STEMI is initially treated with a therapeutic agent with the aim of increasing the likelihood of IRA patency prior to immediate scheduled PCI is described as facilitated PCI. Medications used in this setting include high-dose heparin, GPIIbIIIa inhibitors, fibrinolytic therapy, or reduced-dose fibrinolysis in conjunction with a GPIIbIIIa-inhibiting drug. Possible advantages include more rapid flow restoration, thrombus burden reduction, and restoration of hemodynamic or electrical stability while awaiting PCI. Despite the conceptual appeal of such a management plan, particularly where significant delays may be unavoidable prior to PCI, the 2007 updated ACC/AHA guidelines do not recommend routine facilitated PCI, as it does not offer any evident clinical benefit. However, the guidelines do allow for a facilitated PCI strategy when a high-risk patient with a low risk of a major bleeding complication has received pretreatment with a pharmacologic regimen other than full-dose fibrinolysis (eg, for a patient with a large MI with hemodynamic or electrical instability whose transfer to the catheterization suite would involve a delay). For these patients PCI post fibrinolysis may be most beneficial if performed in the 2- to 24-hour period after administration of pharmacologic reperfusion therapy.

Approximately 5–10% of those undergoing urgent coronary angiography for STEMI are referred for urgent or deferred CABG within several days to weeks post the index event. Patients post fibrinolysis who demonstrate evidence of electrical or hemodynamic instability or recurrent ischemia should be considered for catheterization with a view to revascularization at any time after presentation.

The role of PCI within 12 hours of failed fibrinolytic therapy or rescue PCI is less clear. Guidelines recommend rescue PCI for suitable candidates less than 75 years of age who develop shock within 36 hours of MI and are suitable for revascularization that can be performed within 18 hours of the onset of hemodynamic instability (class IB), and in those with Killip class III heart failure and onset of symptoms within 12 hours (class IB).

In summary, a planned reperfusion strategy using full-dose fibrinolytic therapy followed by immediate PCI is not recommended and may be harmful (class IIIB). PCI of a significant stenosis in a patent infarct artery more than 24 hours after STEMI may be considered as part of an invasive strategy. Rescue PCI for patients who have failed fibrinolytic therapy (defined as less than 50% of ST elevation resolved after 90 minutes following reperfusion drug administration—in the lead with the greatest initial ST-segment elevation) and who have a moderate or large area of myocardium at risk (anterior MI, inferior MI with right ventricular involvement, precordial ST segment depression) is associated with a 28% risk reduction in the composite endpoints of death, reinfarction, and heart failure. PCI of totally occluded artery greater than 24 hours after STEMI is not recommended in asymptomatic patients with one- or two-vessel disease who are hemodynamically and electrically stable with no evidence of severe ischemia (class III).

Is This Patient Experiencing Cardiogenic Shock?

Cardiogenic shock due to acute MI retains a mortality rate of approximately 50%. Risk factors for cardiogenic shock include age greater 70 years, increased time from onset of symptoms of STEMI to presentation, systolic blood pressure (SBP) less than 120 mm Hg, sinus tachycardia greater than 110 beats per minute (bpm) or heart rate less than 60 bpm, and heart failure.

Prognosis of STEMI

Despite the significant advances in reperfusion therapies, the current overall STEMI 30-day mortality rate remains at 6% to 10%. Careful recognition and management of potential MI complications that may have adverse hemodynamic consequences, such as cardiogenic shock (frequently ensuing due to infarction of greater than 40% of the LV mass), RV infarction–induced hypotension or associated atrioventricular dyssynchrony, are vital.

Treatment of UA/NSTEMI

What Is the Short-Term and Long-Term Risk of Adverse Cardiac Events for Patients Experiencing NSTEMI or UA?

The TIMI, GRACE, and PURSUIT risk scores powerfully predict recurrent MI, death, or heart failure in patients with NSTEMI or UA and can be used at the bedside to tailor therapy. Despite proven accuracy, these risk stratification tools are frequently underutilized at the bedside.

The TIMI risk score for NSTEMI

• Age ≥ 65 years
• ≥ 3 risk factors for CAD (family history of CAD, hypertension, hypercholesterolemia, diabetes, current smoker)
• Significant coronary stenosis (stenosis ≥ 50%)
• ST segment deviation
• Severe anginal symptoms (≥ 2 anginal episodes within last 24 hrs)
• Aspirin usage within the previous 7 days
• Elevated serum cardiac biomarkers

Two phase-3 international randomized, double-blind trials totaling over 5000 patients with UA/NSTEMI validated the TIMI (Thrombolysis in Myocardial Infarction) risk score (TIMI-11B and the ESSENCE [Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI]).

Higher TIMI scores are associated with greater risk of all-cause mortality, MI, and worsening ischemia necessitating urgent revascularization through 14 days, as follows:

• Low risk (0–2 points): 4.7 % event rates (0–1 points), 8.3% (2 points)
• Intermediate risk (3–4 points): 13.2% event rates (3 points), 19.9% (4 points)
• High risk (5–7 points): 26.2% event rates (5 points), 40.9% (6–7 points)

The TIMI III registry of over 1100 patients with ACS reinforced the validity of the TIMI scoring system. Six-week mortality increased from 1.0% to 2.9% to 5.9%, and one-year mortality increased from 3.9% to 6.5% to 21.0%, across low, intermediate, and high TIMI score groups. TACTICS TIMI-18 demonstrated that

• Early invasive strategy reduced the composite end point of death, nonfatal MI, or readmission with ACS to 15.9% versus 19.4% at six months.
• Patients in the intermediate and high-risk groups gained most from an early invasive management strategy.
• Patients classified as low risk (< 3 points) derived no benefit from early angiography or PCI.

The GRACE risk score: The Global Registry of Acute Coronary Events (GRACE) risk score uses eight variables that yielded almost 90% of the prognostic information with regard to predicting the probability of in-hospital mortality. Risk factors include age, Killip class (a clinical classification system used in AMI based on the assessment of the patient's hemodynamic status, Table 124-5), SBP, ST-segment deviation, cardiac arrest upon admission, creatinine, biochemical evidence of myocardial necrosis, and heart rate. This risk model has been validated to accurately predict the risk of in-hospital mortality and the cumulative risk of death or MI in those with ACS (including STEMI) in approximately 15,000 patients derived from the GRACE multinational registry (C-statistic = 0.81 for death, C-statistic = 0.73 for death or MI). (An online risk calculator for use with this scoring system is available at www.outcomes.org/grace.)

Does This Patient with UA or NSTEMI Require Urgent Coronary Angiography?

Early coronary angiography allows delineation of the anatomy enabling the physician to rule out ACS in the 10% to 20% of patients with no significant coronary lesion, ensuring that they are not then inappropriately treated. Coronary angiography facilitates prognostic prediction and may appropriately direct patients with multivessel and left main disease to CABG. On the other hand, a considerable proportion of patients respond well to intensive medical therapy, and may not need to undergo an invasive procedure with its associated risks.

The ACC/AHA guidelines recommend coronary angiography leading to revascularization for patients with refractory angina or hemodynamic or electrical instability and for those patients initially managed conservatively who are judged to be at high risk unless there are concomitant severe comorbidities or specific contraindications (class IB).

Patients with higher-risk profiles should undergo catheterization within 48 hours for diagnosis and intervention.

Noninvasive Testing

Contraindications to exercise testing include hemodynamic compromise, acute myocardial infarction or unstable angina, aortic dissection, acute pulmonary embolism, pericarditis or pericardial tamponade, severe anemia, critical aortic stenosis, thyrotoxicosis, pheochromocytoma, and severe uncontrolled hypertension.

The 2007 ACC/AHA guidelines recommend noninvasive testing after 12–24 hours in low- and intermediate-risk patients with either UA or NSTEMI who remain symptom free with no evidence of LV dysfunction. Limited data compare the relative prognostic value of different noninvasive testing modalities in this setting. Options include exercise or pharmacologic stress treadmill testing with or without nuclear imaging, in addition to stress echocardiography depending on the clinical circumstances of the patient (addition of imaging in presence of uninterpretable ECG) and facilities within the institution. Perfusion imaging is preferred for patients whose baseline ECG has ST-segment abnormalities, LBBB, or pacing, and for those who have a significant pretest likelihood for CAD to determine the extent of ischemia. Dobutamine or adenosine are generally reserved for those patients who cannot exercise and do not have contraindications such as severe hypertension (dobutamine) or acute bronchospasm or hypotension (adenosine).

Cardiac-computed tomography (CCT) is able to visualize nonstenotic calcified and noncalcified coronary plaques and has a very high negative predictive value (91% to 100%) of ruling out the presence of CAD. Excellent images may be obtained within five minutes, thereby facilitating rapid triage from the emergency department. Its primary use in acute chest pain should be reserved for patients with an intermediate pretest probability of CAD or for those patients at increased risk for aortic dissection and segmental pulmonary embolism that can be visualized at the same time. Patients with a low pretest probability should not be subjected to the risk of radiation; patients with a high pretest probability of CAD and suspected NSTEMI or UA would not benefit because a negative CCT would not alter the pretest probability.

Cardiac magnetic resonance (CMR) with late gadolinium enhancement may identify specific myocardial regions at risk and thereby provide additive information pertinent not only to risk stratification but also for targeting revascularization in patients with UA/NSTEMI. CMR is a rapidly evolving technology and the reported specificity, positive predictive value, and overall accuracy are likely to improve. The disadvantages of CMR include cost, long time required for scanning, the use of gadolinium in patients with reduced renal function, and contraindications (implanted pacemakers and defibrillators).

Anti-Ischemic Therapy (Class 1 Recommendations)

The ACC/AHA guidelines recommend bed rest for all patients and supplemental oxygen therapy to ensure adequate arterial oxygen saturation. Nonsteroidal anti-inflammatory drugs (NSAIDs), both nonselective and cyclooxygenase-2 (COX-2) selective agents, should be discontinued on admission if possible because they are associated with an increased risk of cardiovascular events in proportion to the degree of COX-2 selectivity. Regular assessment and examination of the patient including blood pressure measurement should be carried out and always prior to drug administration.

Nitroglycerin

Nitroglycerin reduces myocardial oxygen demand by venodilation (decreasing ventricular preload) and by arterial dilation of coronary arteries (improving myocardial oxygen delivery). The ACC/AHA guidelines recommend that all patients should receive nitroglycerin, sublingually or by buccal spray (0.3–0.6 mg) every five minutes for a total of three doses. If the patient's pain persists, intravenous nitroglycerin should be started at an initial rate of 5–10 µg/minute with increases of 10 µg/minute every three to five minutes until the patient is pain free or the SBP falls below 100 mm Hg or more than 30% below initial mean arterial pressure if the patient was hypertensive. Patients receiving sildenafil or other PDE-5 inhibitors should not receive nitroglycerin.

Morphine

In addition to relieving pain and anxiety, morphine may have beneficial effects in treating ACS. The use of morphine remains a class I indication for the relief of pain for patients with STEMI but may increase adverse events in UA/NSTEMI due to hypotension, respiratory depression, or confusion. For the latter, the use of morphine sulfate is a class IIa indication for the relief of ischemic pain when these symptoms do not respond to three doses of nitroglycerin or recur during treatment.

β-Blocker Therapy

β-blockers offer antiarrhythmic and antianginal effects and reduce myocardial contractility and heart rate, thereby decreasing myocardial oxygen demand. Beta-blockers clearly benefit patients with acute MI and are used for the same reasons in patients with ACS. The ACC/AHA guidelines recommend initiating therapy within the first 24 hours after onset of ACS for hypertensive patients unless there is a contraindication (class I recommendation). Contraindications include the presence of heart failure, low-output states, risk factors for cardiogenic shock, PR >0.24, second- or third-degree AV block, bradycardia, hypotension, and cocaine-induced MI. Standard therapy is 5 mg metoprolol IV every five minutes times three doses, followed by 25–50 mg orally every six to eight hours if the patient is hypertensive (class IIa recommendation). Otherwise, oral therapy is prescribed to achieve a target resting heart rate of 50–60 beats per minute. The guidelines recommend caution in the use of IV β-blockers especially for patients at risk of cardiogenic shock (patients with hypotension, tachycardia, and evidence of CHF). Atenolol and propranolol may also be used.

Calcium Channel Blockers

Calcium channel blockers decrease myocardial contractility (reducing myocardial oxygen demand) and vasodilate coronary arteries (improving myocardial blood flow). The ACC/AHA guidelines recommend nondihydropyridine calcium channel blockers (eg, diltiazem, verapamil) for patients who have ischemic symptoms despite full therapeutic doses of nitroglycerin and β-blockers, for patients with Prinzmetal-variant angina, and as an alternative to β-blockers except where there is evidence of LV dysfunction or another contraindication.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers

The ACC/AHA guidelines recommend that angiotensin-converting enzyme (ACE) inhibitors should be given within 24 hours in those with impaired LV function (pulmonary congestion, ejection fraction (EF) < 40%) (class 1 recommendation) and should be considered for patients without impaired LV function (class IIa recommendation). These recommendations are based on a mortality benefit reported when ACE inhibitors were begun within 24 hours of MI. Patients with hypertension, renal insufficiency, diabetes, or persistent heart failure (with EF < 40%) should also receive ACE-inhibitor lifelong therapy unless contraindicated (eg, hypotension, hyperkalemia). Angiotensin receptor blockers (ARBs) are reserved for those who cannot tolerate ACE inhibitors.

Antithrombotic Therapy

Specific antithrombotic therapy (eg, aspirin, clopidogrel, heparin, glycoprotein IIb/IIIa inhibitors) has markedly improved clinical outcomes with ACS.

Inhibitors of Platelet Activation: Aspirin

Aspirin (ASA) irreversibly inhibits COX-dependent platelet aggregation, decreases risk of fatal MI by 70% in the acute phase and 50% to 60% at three months to three years at a dose of 81–325 mg. Although some evidence points toward a significant role for aspirin resistance, aspirin underuse is by far a greater problem in the clinical setting. The international Reduction of Atherothrombosis for Continued Health (REACH) registry reported no antiplatelet therapy in 14% of more than 60,000 patients with CAD. In the absence of an absolute contraindication (active GI bleeding, coagulopathy, or allergy), universal, lifetime ASA should be prescribed following an ACS episode.

Inhibitors of Platelet Activation: Clopidogrel and Other Diphosphate Receptor Blockers

Thienopyridines block adenosine-diphosphate–mediated platelet activation. In healthy volunteers 600 mg of clopidogrel inhibits about 40% of ADP-induced platelet aggregation that was detectable at two hours. After repeated daily dosing (75 mg daily) a steady state is reached where 50% to 60% inhibition occurs. Administration of 600 mg in patients about to undergo coronary angiography yields a full effect after two hours compared with lower loading doses. However, individual patients may exhibit significant differences in response to clopidogrel therapy. For patients who are allergic to aspirin, clopidogrel is an alternative first-line agent and is used as additive therapy for ACS prior to PCI (CURE trial [Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events]). Accepted as preferred therapy for 30 days to prevent stent thrombosis in new nondrug-eluting stents (longer treatment for drug-eluting stents) and as adjunctive therapy after brachytherapy for in-stent restenosis, clopidogrel is preferred over ticlopidine for bioavailability and less agranulocytosis and thrombotic thrombocytopenic purpura (TTP). A 20% relative risk reduction and a 2% absolute reduction (NNT = 50) over one year in the primary end point of MI, stroke, or cardiovascular death occurred with the administration of clopidogrel given as a loading dose (300 mg) with a maintenance dose of 75 mg in addition to ASA compared to ASA alone (CURE trial). Patients with ACS who are intolerant of ASA should be given clopidogrel as a loading dose (usually 300 mg) followed by a maintenance dose of 75 mg daily.

ACC/AHA 2007 guidelines recommend dual antiplatelet therapy with ASA and clopidogrel in those patients undergoing coronary angiography with a view to PCI.

Recently, the thienopyridine prasugrel received FDA approval for use in patients with UA or MI who are undergoing PCI. Like clopidogrel, it binds irreversibly to the platelet ADP P2Y12 receptor but exerts a more potent antiplatelet effect with a significant reduction in the risks of recurrent MI and stent thrombosis compared with clopidogrel (TRITON–TIMI). However, an excess of major bleeding with this new agent was seen with an increased rate of fatal bleeding (approximately 3 per 1000 treated). Remaining issues such as optimal dosing in groups at high risk of bleeding need to be determined, but this antiplatelet agent may prove very useful in managing those undergoing PCI, especially those at high risk of recurrent ischemic events such as stent thrombosis.

Glycoprotein-IIb/IIIa Inhibitors

Platelet aggregation may still occur despite treatment with ASA and ADP antagonists.

GPIIb/IIIa drugs block the final common pathway of platelet activation: the expression of the GPIIb/IIIa receptor. There are three agents: (1) eptifibatide (Integrilin, a peptide) and (2) tirofiban (Aggrastat, a nonpeptide) are small molecules and direct inhibitors of the GPIIb/IIIa receptor; and (3) abciximab (Reopro) is the Fab portion of the human-mouse chimeric antibody directed against the GPIIb/IIIa receptor. Many trials of each agent in UA support the use of tirofiban (PRISM, PRISM-PLUS, TACTICS-TIMI 18) and eptifibatide (PURSUIT) regardless of whether the patient will ultimately undergo cardiac angiography and abciximab (EPIC, EPISTENT, EPILOG, CAPTURE, GUSTO IV-ACS, TARGET) only if cardiac catheterization is planned within 24 hours. Tirofiban is administered as an initial dose of 0.4 µg/kg/minute for 30 minutes, followed by an infusion of 0.1 µg/kg/minute for 48 to 96 hours. Eptifibatide is given as an initial 180 µg/kg bolus, followed by an infusion of 2.0 µg/kg/minute for 72 to 96 hours. Abciximab is given as a bolus (0.25 mg/kg) followed by an infusion (0.125 µg/kg/minute (maximum of 10 µg/minute for 12–24 hours) blocks > 80% of platelet receptors at two hours and requires 12 hours for bleeding times to normalize post intravenous injection. Platelet aggregation usually recovers to normal levels at 48 hours. Abciximab is currently indicated as an adjunctive antiplatelet agent in those patients with ACS/NSTEMI undergoing PCI or planned PCI within 24 hours because abciximab combined with angiography produced the best results, reducing early death by 50%.

Anticoagulants

The ACC/AHA UA/NSTEMI guidelines recommend initiation of anticoagulant therapy for all patients as soon as possible unless there are contraindications (class I recommendations).

Unfractionated Heparin

Unfractionated heparin (UFH), a nonhomogeneous mixture of polysaccharide molecules with an average molecular weight of between 15,000 to 18,000 Daltons, enhances circulating antithrombin III, which in turn inactivates factor IIa, factor IXa, and factor Xa. While it does not break down existing thrombus, it prevents further thrombus formation. A meta-analysis of six randomized controlled trials from 1997 demonstrated a 33% reduction in reinfarction and recurrent ischemia when combined with ASA, although the p value was 0.06. The current recommendations include a weight-adjusted dosing regimen (60 U/kg bolus, followed by a 12 U/kg infusion), monitoring and titration according to a nomogram for target PPT 1.5–2 times the upper limits of normal (ie, approximately 50–70 seconds), aiming lower when given with GPIIb/IIIa antagonists, for at least 48 hours after presentation of UA/NSTEMI. Difficulties with UFH administration include reduced bioavailability at low doses, marked interpatient variability in anticoagulation necessitating activated partial thromboplastin–time (aPPT) measurement, and the complication of heparin-induced thrombocytopenia (HIT) may be outweighed by the ease of reversing the anticoagulant effect of UFH with protamine sulfate, and its short half-life compared with low-molecular-weight heparins (LMWHs) and the pentasaccharide fondaparinux.

Low-Molecular-Weight Heparins

LMWHs (mean molecular weight between 4000 and 5000 Daltons) act predominantly by enhancing antithrombin, but unlike UFH they exhibit reduced thrombin-inactivating properties and have higher ratios of anti-Xa to anti-IIa. Although dalteparin, enoxaparin, and nadroparin have been compared with UFH in clinical treatment trials for UA/NSTEMI, enoxaparin appears to have a clear benefit with a 15% to 20% reduction of death, MI, and urgent revascularization at six weeks (ESSENCE, TIMI 11b). An analysis of six trials that compared enoxaparin with UFH use in almost 22,000 patients with ACS and found enoxaparin to be superior with regard to the 30-day rate of death or MI (10.1% versus 11%; OR 0.91; 95% CI, 0.83 to 0.99). Dalteparin showed an early nonsustained benefit over UFH (FRIC, FRISC, FRISCII trials). FRAXIS failed to show superiority of fraxaparine. Monitoring of anti-Xa levels is generally not advised except in certain clinical instances such as morbid obesity (> 100 kg body weight), renal insufficiency, or pregnancy. Due to their renal excretion the recommended doses require reduction in patients with renal impairment (CrCl < 30ml/minute, 50% of dose). Many operators still prefer UFH because the anticoagulant effect of LMWHs cannot be readily measured in the catheterization laboratory.

Factor Xa Inhibitors

Despite their proven efficacy, neither UFH nor LMWH are thought to be effective attenuating existing clot-bound thrombin. This has prompted the development of more specific anticoagulants. Fondaparinux, a synthetic pentasaccharide, indirectly inhibits factor Xa and requires antithrombin for its action. The ACC/AHA guidelines recommend fondaparinux as treatment for UA/NSTEMI patients unless CABG is planned within 24 hours (class I recommendation). Though less bleeding complications have been reported with this agent compared with enoxaparin, concern remains regarding the increased propensity toward catheter thrombosis during PCI. Fondaparinux is preferred for patients receiving a conservative treatment strategy at increased risk of bleeding (class I recommendation).

Direct Thrombin Inhibitors

Unlike UFH, LMWH, and factor Xa inhibitors, direct thrombin inhibitors do not require a cofactor such as antithrombin in order to inhibit clot-bound thrombin. They do not interact with plasma proteins, and they are not associated with thrombocytopenia. Bivalirudin, a direct thrombin inhibitor, is a hirudin analogue that binds directly to the active site on thrombin. In patients undergoing PCI, it may be given as a bolus dose followed by a continuous infusion during the intervention. It is also used in patients diagnosed with heparin-induced thrombocytopenia who require anticoagulation. It has a short plasma half-life of only 25 minutes after administration and is only partially renally excreted. The ACC/AHA guidelines recommend bivalirudin for patients with UA/NSTEMI undergoing invasive treatment (class I recommendation). In this setting, if a thienopyridine is simultaneously administered with bivalirudin, a GP IIb/IIIa is not required (class IIa recommendation).

For patients directed toward intensive medical therapy without likely coronary intervention, the guidelines advocate enoxaparin or UFH (class IA) or fondaparinux (class IB), while patients managed conservatively, either after coronary angiography or stress testing, should receive UFH for 48 hours or enoxaparin or fondaparinux for the duration of hospitalization or up to eight days (class IA). ACC/AHA guidelines recommend that enoxaparin or fondaparinux over UFH as anticoagulant therapy for patients with UA/NSTEMI receiving conservative management unless CABG is planned within 24 hours (class IIa recommendation). The benefit of enoxaparin appears to be greater for patients at higher risk (eg, ST-segment abnormalities, elevated cardiac biomarkers, high TIMI risk scores). Enoxaparin and UFH have a class IA recommendation for patients likely undergoing PCI, while bivalirudin and fondaparinux have a class IB recommendation in this setting.

Oral Anticoagulation

Warfarin does not offer any additional benefit over clopidogrel plus aspirin, although combination therapy with aspirin is superior to aspirin alone. The benefit of dual antiplatelet therapy with aspirin and clopidogrel is clear for patients who undergo PCI and stenting. Therefore, warfarin is usually reserved for patients with other indications such as stroke prophylaxis (eg, atrial fibrillation, mechanical prosthetic valve, left ventricular thrombus) with a target INR of 2–2.5 in addition to dual antiplatelet therapy with 81 mg of aspirin and 75 mg of clopidogrel for various periods of time depending on patient risk.

Lipid-Lowering Therapy

Statins should be prescribed for all patients with UA/NSTEMI irrespective of baseline LDL cholesterol levels. The Adult Treatment Panel III guidelines and the 2007 ACC/AHA guidelines recommend dosage titration to lower the LDL cholesterol to < 70 mg/dl (class IIa recommendations). The benefit in endpoints of all-cause death, MI, UA requiring rehospitalization, or revascularization and stroke appears to be linked to statistically significant decreases in the LDL cholesterol and C-reactive protein (CRP).

A summary of the key drugs used in the initial management of ACS is provided in Table 124-6.

After stabilization and treatment of ACS, continued clinical management is required for prevention of ischemia and to maximize secondary prevention. Therapy should include antiplatelet agents, beta-blockers (if intolerant, calcium channel blockers), ACE inhibitors or ARBs (class IA for LVEF < 0.4, IIA for LVEF > 0.4), and statins. Nitrates are also indicated to treat symptoms of ischemia. Patient education covering modifiable risk factors (eg, exercise, smoking, diabetic control, blood pressure) and symptom-recurrence awareness is vital. Target goals for HbA1c should be less than 7. Target goals for lipids should be LDL less than 70, HDL greater than 40, and triglycerides less than 150. Particular emphasis should be placed on compliance with dual antiplatelet agents in the post coronary artery–intervention setting. Aspirin (75–162 mg per day) should be continued indefinitely with the addition of clopidogrel 75 mg per day for one month in those managed medically (class IA). Continuation of clopidogrel for up to 1 year is given as a class IB recommendation. Patients who underwent stenting should take aspirin at a higher dose of 162–325 mg daily for the first month, and clopidogrel at 75 mg per day should be given for at least 1 month and ideally for 12 months. Those with drug-eluting stents require clopidogrel for a longer duration and a minimum of 12 months. Consideration should also be given to the need for an automated implantable cardiac defibrillator (AICD) in those with LV dysfunction. AICD placement should not be considered in the first 40 days following an acute MI (despite LV dysfunction), as trial data demonstrate no benefit to this intervention in the early post-MI period.

Current guidelines advocate that primary PCI for STEMI, in a hospital with PCI capability, should be performed within 90 minutes of first contact (class IA). The practical implementation of this involves the close integration of a number of services (EMS, ED, interventional cardiology, and others). A successful model utilizes a STEMI committee to incorporate regular performance analysis and ensure target guidelines are met. Hospitalists may play a critical leadership role in improving access to primary PCI through early recognition of ACS at their community hospitals and through teamwork. In addition, hospitalists may improve provider-patient communication by taking the following steps:

1. Address disparities in health care, including facilitating access for free care for those in need.

2. Ensure patient education about the importance of therapy (eg, dual antiplatelet therapy, lifelong ASA therapy), risk-factor modification, and prescribe simple and cost-conscious drug regimens that facilitate compliance.

3. Arrange appropriate follow-up even for patients who have no evidence of CAD but have modifiable risk factors.

4. Provide availability to patients should questions arise prior to their follow-up appointments with their primary care physicians.

Hospitalists should also effectively communicate with receiving primary care physicians at the transition of care and ensure appropriate and timely follow-up.

Major progress has been made over the past three decades, from the establishment of coronary care units to exciting antiplatelet and antithrombotic drug developments. These have been complemented by the tremendous growth and refinement of percutaneous coronary intervention with the hope of reducing the major morbidity and mortality of cardiovascular diseases. This progress has led to a greater than 50% reduction in age-adjusted death rates for coronary heart disease in the U.S. since 1965. Despite the fact that advances in every aspect of the clinical management of patients with ACS continue unabated, opportunities to eliminate performance gaps require a coordinated team approach.