Joel Kupersmith M.D., F.A.C.P.1
Amish Raval M.D.2
1Professor of Internal Medicine, Texas Tech University School of Medicine
2Interventional Cardiology Fellow, Georgetown University, Fellow, Division of Cardiology, Georgetown University School of Medicine
The authors have no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
February 2004
Definition
Acute coronary syndromes are the constellation of symptoms, signs, and electrocardiographic and laboratory findings associated with new-onset or worsening myocardial ischemia. They include the spectrum of acute ST segment elevation myocardial infarction (MI) with or without Q waves, non-ST segment elevation MI (NSTEMI), and unstable angina. The main difference between NSTEMI and unstable angina is that in the latter, the ischemia is not severe enough to cause cardiac enzyme elevation and tissue injury; however, this difference may not be apparent on initial presentation.1,2
Pathophysiology
Unstable angina/NSTEMI results from an acute reduction in myocardial oxygen supply caused by rupture or erosion of an atherosclerotic coronary plaque; this plaque disruption is associated with inflammation, thrombosis, vasoconstriction, and microvascular embolization. The plaques implicated in these syndromes usually had previously produced only minor obstruction to blood flow (on angiography, up to 70% of affected vessels have less than 50% stenosis of the lumen); in addition, these plaques are characterized by a large lipid pool, reduced collagen content, a thin fibrous cap, and inflammatory cells.3,4,5,6,7,8,9 Embolization of platelets and clot fragments into the microvasculature results in microcirculatory ischemia, which may account for the slight elevation of cardiac biomarkers. The events leading to unstable angina/NSTEMI also affect atherosclerotic plaques in the rest of the coronary vascular tree and other vascular territories.10,11,12
Less common causes of unstable angina/NSTEMI include intense focal epicardial spasm, cardiac emboli, and severe progressive atherosclerotic narrowing without superimposed thrombus.1 Rarely, secondary unstable angina can be precipitated by conditions that increase myocardial demand, such as thyrotoxicosis, sepsis, fever, tachycardia, and anemia. Secondary unstable angina usually occurs in patients who also have underlying stable coronary atherosclerosis. Cocaine and amphetamines can also induce the syndrome.
Diagnosis
CLINICAL PRESENTATION
Unstable angina/NSTEMI has three principal presentations: (1) prolonged angina at rest, usually lasting less than 20 minutes; (2) new-onset angina that is severe, disabling, and prolonged or frequent; and (3) established angina that has become distinctly more frequent, longer in duration, or more easily provoked.13
HISTORY AND PHYSICAL EXAMINATION
Five clinical factors are key to establishing the diagnosis and the prognosis in patients with suspected unstable angina/NSTEMI: the anginal symptoms; any history of coronary artery disease (CAD); patient sex; patient age; and traditional risk factors for CAD [see Table 1].1
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Table 1 Clinical Factors for Determining Diagnosis and Prognosis in Patients with Suspected Unstable Angina or Non-ST Segment Myocardial Infarction |
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In the initial evaluation of a patient with suspected unstable angina/NSTEMI, the clinician should elicit a full description of the chest pain, including its character, onset, severity, and duration. Jaw pain, neck pain, epigastric pain, and arm pain may be experienced in isolation or in concert with the chest discomfort. In the National Registry of Myocardial Infarction, which included 440,000 patients, one third had atypical symptoms.14 In the Alabama Unstable Angina Study of Medicare beneficiaries, which included over 4,000 patients, 51.7% of patients with unstable angina had the following atypical symptoms: dyspnea (69.4%), nausea (37.7%), diaphoresis (25.2%), syncope (10.6%), arm pain (11.5%), epigastric pain (8.1%), shoulder pain (7.4%), and neck pain (5.9%).15 Atypical symptoms were more common in young patients (i.e., those 25 to 40 years of age), the elderly (i.e., those older than 75 years), diabetic patients, and women.14
Although it is important to inquire about the traditional risk factors for CAD, both to assess current risk and to guide future risk reduction, these factors are only weakly predictive of unstable angina/NSTEMI.1 Important secondary or precipitating causes of unstable angina/NSTEMI should be ruled out, including a history of cocaine or amphetamine abuse, severe hypertension, and hyperthyroidism. Myopericarditis, hypothyroidism, and renal failure are among the conditions that may mimic acute coronary syndrome and can be associated with elevated cardiac enzyme levels.
In many cases, the physical examination will be normal. The examination is nevertheless useful to establish the presence of certain prognostic factors for the purpose of risk stratification and also to rule out such potentially devastating conditions as aortic dissection, pulmonary embolus, pneumothorax, and pericarditis.
The pulse is carefully evaluated to assess for significant bradycardia, tachycardia, or irregularity. Blood pressure is measured, to look for uncontrolled hypertension or significant hypotension (suggesting cardiogenic shock); pressure should be measured in both arms, to assess for aortic dissection [see 1:XII Diseases of the Aorta]. Examination of the thyroid may suggest hypothyroidism or hyperthyroidism. Heart failure should be suspected if there is evidence of pulmonary rales, an elevated jugular venous impulse, an S3 gallop, or a displaced and diffuse apical impulse. A murmur of acute mitral regurgitation may be a consequence of ischemia. Thrills, bruits, or pulse deficits may indicate coexisting peripheral vascular disease.
LABORATORY TESTS
Biochemical Cardiac Markers
Cardiac biomarkers—specifically, troponins, cardiac creatine kinase, and myoglobin—have important diagnostic, prognostic, and therapeutic implications in unstable angina/NSTEMI and for detection of MI generally. After ischemia-induced myocardial injury, loss of myocyte membrane integrity results in the release of various intracellular molecules into the interstitial space, lymphatics, and, eventually, into the peripheral circulation. Critical to the interpretation of these tests is the precise time of onset of ischemic symptoms.
Troponin
Troponin I and T (TnI and TnT) are cardiac-specific subunits of the thin filament-associated troponin-tropomyosin complex, which regulates striated muscle contraction. Troponins have become the primary biomarkers in the evaluation of patients with acute coronary syndromes. These markers are detected in about one third of patients without elevation in the level of creatine kinase-myocardial band (CK-MB). Troponins may be detectable 3 to 4 hours after the onset of ischemic symptoms; they peak at 12 to 48 hours and persist for 4 to 10 days.16,17 Generally, they are not detectable in the blood of healthy persons. However, both TnI and TnT are exceptionally sensitive to the presence of even minor myocardial necrosis, such as in supraventricular tachycardia, heart failure, and myocarditis, and they may also be elevated in severe renal impairment. Therefore, they should be evaluated in the context of the patient's clinical presentation.
Creatine kinase
Before the advent of troponin assays, CK-MB was the primary cardiac biomarker. The CK-MB assay has considerable sensitivity and specificity for detecting myocardial necrosis at 6 to 48 hours after symptom onset or earlier. Abnormal CK-MB levels can be occasionally found in patients with high total CK levels; on clinical grounds, the CK-MB in such cases is thought to originate from skeletal muscle. Elevations in levels of the CK-MB isoforms CK-MB2 and CK-MB1 are very early markers of myocardial necrosis, but these assays are generally not part of the clinical routine.18
Myoglobin
Myoglobin is a nonspecific biomarker found both in cardiac and skeletal muscle. It is released rapidly in response to muscle injury and is detectable 2 hours after the onset of ischemia.17 Serial determination of myoglobin is not useful, but because of its high sensitivity in early ischemia, a negative myoglobin assay could potentially rule out myocardial necrosis.
Twelve-lead electrocardiogram
ECG results may be important for determining treatment; patients with acute ST segment elevation should be considered for immediate reperfusion therapy.19 In patients with suspected unstable angina/NSTEMI, ST segment depression of 0.05 mV or more in two or more contiguous leads is highly consistent with myocardial ischemia (this is especially the case if the ST segment depression is present during chest pain and resolves with the easing of pain). Deep, symmetrical T wave inversion is also highly consistent with myocardial ischemia. Other nonspecific abnormalities, such as transient bundle branch block, atrial or ventricular arrhythmias, and QT prolongation, can also occur with unstable angina/NSTEMI but are not useful for diagnosis. Interestingly, a quarter of patients diagnosed with unstable angina/NSTEMI will go on to develop Q waves,2 and up to 60% may have a normal 12-lead ECG.20
RISK STRATIFICATION
Determining whether a patient is at low, medium, or high risk for ischemic complications (e.g., full-blown MI) is important for deciding treatment of unstable angina/NSTEMI. Depending on whether the therapeutic strategy will be invasive or conservative (see below), the degree of risk can be used to determine the level of therapy. Older age, positive cardiac biomarkers, rales, ST segment depression, hypotension and tachycardia,21 and reduced left ventricular ejection fraction (< 40%) have been associated with increased mortality. Clinical diabetes mellitus is also associated with higher risk. One specific and widely used method of risk stratification, the Antman/Thrombolysis in Myocardial Infarction (TIMI) risk score, is a seven-point scoring system that helps to predict death, reinfarction, or recurrent ischemia requiring revascularization [see Table 2].22 This risk score was developed from the TIMI IIB23 and Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE)24 trial and has been validated in two other large trials: Therapy with an Invasive or Conservative Strategy—Thrombolysis (TACTICS)-TIMI 18 and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS).25,26 The risk of adverse outcomes ranges from 5% to 41%, according to the simple sum of the individual variables.
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Table 2 Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Unstable Angina or Non-ST Segment Myocardial Infarction* |
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Electrocardiographic Changes
Patients with unstable angina/NSTEMI and ECG findings of bundle branch block, ventricular hypertrophy, paced rhythm, or severe ST segment depression (> 0.2 mV) in multiple leads are independently at high risk for subsequent adverse events.1,20 Considered at low risk are those with isolated T wave abnormalities or a normal ECG pattern. Continuous ECG monitoring may detect transient ischemic episodes, which have been shown in small studies to have prognostic value, but the use of this technique as a risk marker is not widely recommended.1,27,28
Blood Tests
Both TnI and TnT are markers of increased risk in that they reflect the presence and level of myocardial necrosis.1,16 High-sensitivity C-reactive protein (hsCRP), which is produced by the liver in response to inflammation,29,30 and other acute-phase reactants such as plasma fibrinopeptide, fibrinogen, serum amyloid A, and interleukin-6, have demonstrated similar predictive value for adverse outcomes.31,32,33 B-type natriuretic peptide (BNP), released in response to ventricular wall stress, may also independently predict mortality.34 Measurement of hsCRP and BNP may be of use at times, but more studies are needed to clarify the roles of these markers in routine care.
Stress Testing
Stress testing for assessment of risk may be performed in patients who have been stable and asymptomatic for 24 to 48 hours and in all patients before discharge. Stress testing is a necessary component of an early conservative strategy (see below). Briefly, stress test results that show the patient to be at high risk for significant ischemia are as follows:
Treatment
WHERE TO HOSPITALIZE
In most medical centers in the United States, patients with definite features of unstable angina/NSTEMI are admitted to a cardiac care unit that provides continuous ECG monitoring and specialized nursing. Patients with less than definite features of unstable angina or those in whom the chest pain has ceased by the time of arrival may be admitted to a chest pain unit with telemetry (sometimes called a step-down cardiac unit).
Ideally, patients with unstable angina/NSTEMI should be hospitalized in an institution that offers mechanical revascularization, because these procedures are frequently needed in such patients, especially those who have high-risk features. If this is not possible, high-risk patients should receive interim treatment with an intensive pharmacologic regimen until arrangements can be made for transfer to a facility with interventional capability.
INITIAL THERAPY
The initial management of unstable angina/NSTEMI includes resuscitation and supportive measures for patients who present with hemodynamic instability, as well as prompt administration of medication of proven, evidence-based value [see Pharmacologic Therapy,below, and [see Figure 1]. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection is a class I recommendation for patients who have ongoing anginal pain at rest, on the basis of level C evidence [see Table 3]. The strictness of the bed rest requirement can be tailored to the severity of symptoms. For instance, patients can be mobilized to a chair or bedside commode when symptom free.
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Figure 1. Diagnostic and Management in Unstable Angina Diagnostic and management steps in patients with unstable angina or non-ST segment elevation myocardial infarction (UA/NSTEMI). (LMWH—low-molecular-weight heparin; MI—myocardial infarction) |
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Table 3 Recommendation Classes and Evidence Levels1 |
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Oxygen
Inhaled oxygen therapy should be reserved for those patients with clear respiratory distress, cyanosis, or arterial hypoxemia. In the absence of these high-risk features, time and resources need not be spent for the sole purpose of oxygen administration. Supplemental oxygen is recommended for patients with cyanosis or respiratory distress. Finger pulse oximetry or arterial blood gas measurements should be done to determine whether the patient has adequate arterial oxygen saturation (SaO2 > 90%) or has hypoxemia and requires supplemental oxygen. These class I recommendations are supported by level C evidence.
EARLY INVASIVE VERSUS EARLY CONSERVATIVE STRATEGY
The first decision in management (and one that is often a matter of dispute) is to choose between the two reigning strategies for unstable angina/NSTEMI: early invasive management and early conservative management [see Figures 2 and 3]. In the early invasive strategy, early coronary angiography is performed unless contraindicated. In the early conservative strategy, angiography is reserved for those patients who have indications of being at high risk for cardiac events; such indications include evidence of significant ischemia on a noninvasive stress test and recurrent ischemia despite adequate medical therapy. It should be noted that although many patients assigned to the conservative strategy undergo angiography and receive interventions (e.g., in one study, 51% of patients underwent angiography and 36% received subsequent revascularization25), in these patients there was an additional indication for the angiography, based on risk, besides the diagnosis of unstable angina/NSTEMI.
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Figure 2. Early Invasive Strategy Early invasive strategy in unstable angina or non-ST segment elevation myocardial infarction. (CABG—coronary artery bypass grafting; GPIIa-IIIb, glycoprotein IIa-IIIb; LMWH—low-molecular-weight heparin; PCI—percutaneous coronary intervention) |
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Figure 3. Early Conservative Strategy Early conservative strategy in unstable angina/non-ST segment elevation myocardial infarction. |
Advocates of an early conservative strategy suggest that angiography—and its associated risks—can be avoided in low-risk patients and that costs and resources can be conserved by not performing these procedures in all patients. Advocates of an early invasive strategy suggest that this approach can result in superior clinical outcomes through early identification of patients with high-risk lesions, including those with critical left main coronary artery stenosis or triple-vessel coronary disease. In addition, advocates of an early invasive strategy argue that such intervention results in shorter hospital stays for patients found to have low-risk anatomy; these proponents also note that cardiac catheterization is now available to almost all patients and that catheterization has a very low procedural risk.
Trial Results
Three initial multicenter, randomized trials found that there was no difference in outcome between an early invasive strategy and an early conservative strategy, whereas three subsequent trials showed benefit in favor of the invasive strategy. TIMI IIIB showed no difference in death or MI at 42 days with either strategy in patients with unstable angina/NSTEMI36; the Veterans Affairs Non-Q-Wave Myocardial Infarction Strategies In-Hospital (VANQWISH) trial showed no difference in death or recurrent MI in the early invasive versus the conservative group at 2 years' average follow-up (32.9% versus 30.3%; P = 0.35), although there were more deaths in the early invasive group at 1 year37; and the Medicine versus Angiography in Thrombolytic Exclusion (MATE) trial, conducted in patients with acute coronary syndrome who were ineligible for thrombolysis, showed no difference in clinical outcome between either strategy.38
The three subsequent studies have begun to move opinion toward the invasive strategy. The Fragmin in Unstable Coronary Artery Disease II (FRISC II) study was conducted in patients with unstable angina/NSTEMI who were receiving dalteparin; death or MI occurred in 9.4% of patients who received invasive treatment, as compared with 12.1% of those treated conservatively (P < 0.031; risk ratio, 0.78; confidence interval, 0.62 to 0.98).39 However, a substudy of FRISC II showed that the most benefit of the early invasive strategy accrued to those patients with an ST segment shift of more than 2.5 mm or in five or more leads.40 The Therapy with an Invasive or Conservative Strategy-Thrombolysis—TIMI 18 (TACTICS-TIMI 18) trial involved patients with unstable angina/NSTEMI who had ST or T wave changes, increased cardiac markers, and a history of coronary artery disease and who were taking aspirin, heparin, and tirofiban. This trial showed a combined end point (death, MI, or rehospitalization at 6 months) of 15.9% in the early invasive group, as compared with 19.4% in the early conservative group (P = 0.025; relative risk, 0.78; confidence interval, 0.62 to 0.97). Major bleeding was similar in both groups (1.9% versus 1.3%; P = 0.24). Subgroup analysis of the trial suggested that early invasive treatment benefited only patients whose TnI or TnT level was initially elevated.41 Of note, median length of stay was somewhat shorter with the invasive strategy (3.9 days versus 4.3 days; P< 0.001). The cost of care in the invasive group was somewhat higher for the initial hospitalization ($15,714 versus $14,047 in year 2000 dollars), though the 6-month average total costs did not differ between the two groups ($21,813 for the invasive group versus $21,227 for the conservative group; P = nonsignificant).42 In the Randomized Intervention Trial of unstable Angina-3 (RITA-3) in unstable angina/NSTEMI patients treated with enoxaparin, rates of death or MI at 4 months were lower in the early invasive group (9.6% versus 14.5%; P = 0.001; relative risk, 0.66; confidence interval, 0.51 to 0.85).43
Although the results of these three trials differed, patients who were considered to be at high risk for death or MI consistently seemed to benefit the most from a strategy of early angiography and revascularization. Because of the low event rate in patients considered to be at low risk, it is not clear that the early invasive approach offers a clear advantage over an early conservative strategy for this population. Therefore, until further evidence becomes available, an early conservative strategy may be a reasonable initial approach for the management of low-risk patients with unstable angina/NSTEMI.
Treatment Recommendations
High-risk patients
A class I recommendation and level A evidence support the use of an early invasive strategy in patients with unstable angina/NSTEMI who have no serious comorbidity and have any of the following high-risk indicators:
In the absence of any of these findings, either a conservative or an invasive strategy may be offered to hospitalized patients without contraindications for revascularization. This option is supported by a class 1 recommendation and level B evidence.
Women and the elderly
There should be no difference in the management of men and women. The elderly should be treated no differently than younger patients, although management should take into consideration general health, comorbid conditions, cognitive status, life expectancy, and altered pharmacokinetics of and sensitivity to hypotensive drugs.
PHARMACOLOGIC THERAPY
Antiplatelet Drugs
Antiplatelet medications used in unstable angina/NSTEMI include aspirin, thienopyridines (clopidogrel and ticlopidine), abciximab, eptifibatide, and tirofiban [see Table 4].
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Table 4 Antiplatelet Therapy in Unstable Angina or Non-ST Segment Elevation Myocardial Infarction |
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Aspirin
Aspirin is considered the benchmark antiplatelet agent for the treatment of unstable angina/NSTEMI. A class I recommendation and level A evidence suggest that aspirin be started immediately in these patients and continued indefinitely.1,2
Aspirin's mechanism of action is to decrease the formation of the potent platelet aggregator thromboxane A2 by irreversibly binding cyclooxygenase-1 in platelets. The effect on platelets is rapid (occurring within 15 to 30 minutes), and it is achieved with an oral dose as low as 81 mg.
Four pivotal randomized trials that evaluated the effectiveness of aspirin in the treatment of acute coronary syndrome showed consistent and durable long-term benefit at doses ranging from 75 to 325 mg daily.44,45,46,47 The Antiplatelet Trialists' Collaboration meta-analysis of more than 100,000 patients in 145 trials showed such benefits in several cardiovascular disorders. For example, in 4,000 patients with unstable angina, rates of so-called vascular events (nonfatal MI, nonfatal stroke, or vascular death) were reduced from 14% to 9% (P < 0.00001) after 6 months.48 Furthermore, the benefit of aspirin in these high-risk patients was sustained for at least 2 years.
Aspirin dosages have varied among several trials; no dosage has been definitively shown to be preferable. For patients with suspected MI in the International Studies of Infarct Survival-2 (ISIS-2) trial, the effective dosage was 160 mg daily.49 A dose of aspirin between 160 and 325 mg should be administered immediately; the first dose should be chewed, for rapid absorption, and subsequent doses swallowed.
Adverse effects of aspirin include allergy, which may manifest as rash, angioedema, or asthma; a tendency to bleed; gastrointestinal effects, including gastric ulcer; and, rarely, precipitation of acute gout. Contraindications include allergy (especially if the allergic reaction is in the form of asthma), active bleeding, a serious bleeding disorder, severe untreated hypertension, and an active peptic ulcer.
Thienopyridines
Thienopyridines irreversibly bind the adenosine diphosphate receptor on platelets, preventing fibrinogen binding and platelet aggregation. The two thienopyridines that have been used clinically are ticlopidine (Ticlid) and clopidogrel (Plavix).
In a single open-label trial in patients with unstable angina, ticlopidine (250 mg twice daily) significantly reduced vascular death and nonfatal MI at 6 months (13.6% versus 7.3%; P = 0.009), compared with standard aspirin therapy.50 Several trials have shown the value of clopidogrel. In 12,562 patients with unstable angina, all of whom were also treated with aspirin, clopidogrel (300 mg followed by 75 mg daily), administered for 3 to 12 months, reduced a combined end point of cardiovascular death, nonfatal MI, and stroke from 11.4% to 9.3% (P < 0.001) and also decreased the incidence of ischemia, heart failure, and revascularization procedures. Benefit occurred as early as 24 hours after initiating treatment and persisted for up to 1 year. Clopidogrel increased major bleeding from 2.7% to 3.7% (P = 0.003), but there was no difference in life-threatening bleeding or hemorrhagic shock. Importantly, bleeding was increased in patients who underwent CABG within 5 days after stopping clopidogrel.51 Two other studies found that clopidogrel benefited patients treated with percutaneous coronary intervention.52,53 The Clopidogrel for the Reduction of Events During Observation (CREDO) study examined the timing of therapy with a combination of clopidogrel and aspirin. In one arm of the study, patients received a bolus load of aspirin and clopidogrel 6 to 24 hours before undergoing percutaneous coronary intervention. In the other arm of the study, patients received a bolus load less than 6 hours before the procedure. Benefit was observed in those patients who received the bolus 6 to 24 hours before the procedure.
The dosage of ticlopidine is 250 mg orally, twice daily; the dosage of clopidogrel is 300 mg orally. Both agents should be started immediately on presentation. The duration of therapy, which has been better defined for clopidogrel, is up to 1 year at a dose of 75 mg daily.
The principal adverse reaction that has limited the clinical use of ticlopidine is severe neutropenia; rarely, thrombotic thrombocytopenic purpura develops within the first 3 months of therapy. Both conditions are life threatening unless the drug is discontinued promptly. Clopidogrel has been associated with increased bleeding complications when administered with other antithrombotic agents, particularly when arterial puncture is performed for intervention. Bleeding during surgery is an important complication of clopidogrel use; for this reason, surgery should be avoided for 5 and preferably 7 days after the last dose, because of the prolonged duration of action.
Recommendations for the use of clopidogrel are as follows:
Glycoprotein IIb-IIIa receptor antagonists
Abciximab, eptifibatide, and tirofiban act by specifically binding the glycoprotein (GP) IIb-IIIa receptor on platelet surfaces, thereby preventing fibrinogen binding and ultimately preventing platelet aggregation. Abciximab is the Fab fragment of a monoclonal antibody that has a short plasma half-life but irreversibly binds the GPIIb-IIIa receptor for 24 to 48 hours. The half-lives of eptifibatide and tirofiban are 2 to 3 hours, with platelet aggregation returning to normal 4 to 8 hours after drug discontinuance.
In three large clinical trials of patients with unstable angina/NSTEMI who underwent percutaneous coronary intervention, all of these GPIIb-IIIa inhibitors provided significant benefit in the composite outcome of death, MI, or urgent repeat revascularization, with the major benefit seen in recurrent MI and urgent repeat revascularization.26,54,55 The Do Tirofiban and Reopro Give Similar Efficacy Trial (TARGET), which was conducted in patients with unstable angina/NSTEMI who underwent percutaneous coronary intervention with stenting, found that abciximab conferred greater benefit than tirofiban (although tirofiban was administered at a suboptimal dosage).56
For patients not undergoing planned percutaneous intervention, the results with GPIIb-IIIa inhibitors have been less impressive. Abciximab, given for 24 or 48 hours, was found to be no better than placebo in the Global Use of Strategies to Open Occluded Coronary Arteries IV (GUSTO IV) trial in patients with acute coronary syndrome.57 On the other hand, two trials with tirofiban and eptifibatide demonstrated modest benefit in patients who did not undergo an interventional procedure26,54; the benefit was greatest in high-risk patients.
Abciximab, which is recommended for use during percutaneous coronary intervention, is administered as a 0.25 mg/kg intravenous bolus, followed by an infusion at 0.125 µg/kg/min for 12 hours. Eptifibatide is administered as a 180 µg/kg intravenous bolus, followed by a second bolus after 10 minutes. Thereafter, it is infused at a rate of 2 µg/kg/min for 72 to 96 hours if no percutaneous intervention is performed or for 18 hours if such a procedure is performed. Tirofiban is given in an intravenous 0.4 µg/kg/min bolus over 30 minutes, then infused at a rate of 0.1 µg/kg/min for 48 hours.
Bleeding is the most common complication of GPIIb-IIIa inhibitors. Special care should be taken to prevent bleeding in high-risk patients such as the elderly, women, those with low body weight, and those who require arterial puncture for an intervention. Because of their short half-lives, eptifibatide or tirofiban may be better suited for patients who may require surgical revascularization. Abciximab results in serious thrombocytopenia in about 0.3% of patients,56 so serial platelet measurements are recommended in patients receiving this agent. In a meta-analysis, GPIIb-IIIa inhibitors were found to increase major bleeding from 1.4% to 2.4 % (P < 0.0001). There was no increase in the rate of intracranial hemorrhage.58
Three evidence-based recommendations can be made for the use of GPIIb-IIIa inhibitors:
Fibrinolytic Drugs
Fibrinolytic therapy is not indicated for patients with unstable angina/NSTEMI. Level A evidence indicates that intravenous fibrinolytic therapy should not be administered to patients who do not have acute ST segment elevation, unless they have a true posterior MI or a presumed new left bundle branch block (class III recommendation).59
Anticoagulants
Heparin, low-molecular-weight heparin (LMWH), bivalirudin, or warfarin can be used for anticoagulant therapy in patients with unstable angina/NSTEMI [see Table 5].
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Table 5 Anticoagulant Therapy in Unstable Angina/ Non-ST Segment Elevation Myocardial Infarction |
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Heparin
Unfractionated heparin is composed of a number of chains of varying molecular weights that differ with regard to anticoagulant activity. Heparin generally increases the action of circulating antithrombin, which inactivates factor IIa, factor IXa, and factor Xa and prevents thrombus formation.60
Three randomized, placebo-controlled trials suggested that early intravenous administration of heparin leads to a modest reduction in the incidence of MI or recurrent ischemia.61,62,63 A meta-analysis of six trials showed a relative risk of 0.67 (95% confidence interval, 0.44 to 1.02) in favor of the combination of heparin and aspirin.64
Heparin should be given in an initial intravenous bolus of 60 to 70 U/kg (maximum, 5,000 U), followed by an infusion of 12 to 15 U/kg/hr (maximum, 1,000 U/hr). Doses should be adjusted to maintain an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times control values.1
As with any anticoagulant, heparin is contraindicated in patients with active severe bleeding or who are to undergo imminent surgery. Heparin-induced thrombocytopenia (HIT) is a serious but rare (< 0.2% incidence) antibody-mediated reaction leading to reduced platelet counts and thrombosis [see 5:XIV Thrombotic Disorders]. HIT mandates immediate cessation of heparin, including heparinized solutions used for the flushing of intravenous ports. From 10% to 20% of patients receiving heparin may experience mild thrombocytopenia that is not associated with severe thrombosis or excessive bleeding.1 For serious bleeding, heparin anticoagulation can be immediately reversed with intravenous protamine sulfate.
Low-molecular-weight heparin
LMWHs are produced by enzymatic depolymerization of unfractionated heparin, resulting in smaller chain units. Advantages include less protein binding; longer half-life; more stable, dose-dependent clearance; and a greater anti-factor Xa effect that is associated with more thrombin inhibition. The standard aPTT assay cannot be used for LMWH, because this assay is not sensitive to the anti-Xa effects of LMWHs. Rapid factor Xa assays are not widely available, but the stable kinetics of LMWH tends to reduce the need for monitoring.
A number of trials have compared individual LMWHs with unfractionated heparin. Meta-analysis of two trials revealed a modest benefit of enoxaparin over heparin in terms of death and MI at 45 days (7.1% versus 8.6%; P = 0.02).65 In trials with dalteparin and nadroparin, neither showed benefit.66,67 FRISC showed a significant improvement in death, MI, or urgent revascularization with dalteparin (1.8% versus 4.8%; P = 0.001) for up to 43 days.68 In the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) trial, enoxaparin was found to be associated with less ischemia, as evidenced on ECG (14.3% versus 25.4%; P = 0.002), and to lead to an improvement in the composite end point of death or MI at 30 days (5% versus 9%; P = 0.031).69 Several trials showed evidence of a small increase in minor bleeding with LMWH, as compared with heparin, but no difference in major bleeding was seen.66,67,68,69 One small trial demonstrated that enoxaparin was safe with regard to serious bleeding in unstable angina/NSTEMI patients undergoing percutaneous coronary intervention.70 Another trial showed significantly lower rates of major CABG-related bleeding with LMWH, as compared with enoxaparin, by 96 hours after percutaneous coronary intervention (1.8% versus 4.6%; P = 0.03).23 When enoxaparin was added to abciximab, no difference in the rate of bleeding events and adverse ischemic outcomes was seen, as compared with historical controls.71
In summary, evidence to date suggests that LMWH is at least as effective as unfractionated heparin and is generally safe in patients with unstable angina/NSTEMI in whom surgery or percutaneous coronary intervention is not planned. The dosing of LMWH is simpler than that of unfractionated heparin, and LMWH therapy does not require monitoring with coagulation studies. Abundant data (e.g., from the TIMI 11B, ESSENCE, and INTERACT studies) suggest that enoxaparin is the preferred agent.23,24,69 In patients for whom percutaneous coronary intervention is planned, LMWH may be started or continued, provided that meticulous attention is given to dosing and the timing of its administration. Enoxaparin has not found wide use in contemporary interventional practice, however, because of practitioners' uneasiness over the inability to monitor the level of anticoagulation. In patients in whom surgery is planned, LMWH should be avoided; if an LMWH has already been started, the patient should be switched to unfractionated heparin, whose effects can be monitored closely.
Enoxaparin is given subcutaneously at a dosage of 1 mg/kg every 12 hours for at least 48 hours. Percutaneous coronary intervention may be performed within 8 hours of starting the drug, without additional anticoagulation therapy. If the percutaneous procedure is performed 8 to 12 hours after starting the drug, an additional intravenous bolus of 0.3 mg/kg may be given. Dose adjustment must be made in patients with moderate to severe renal impairment.
Compared with unfractionated heparin, LMWH has a slightly higher rate of minor bleeding complications and the same rate of major bleeding complications. Although the risk of HIT seems to be lower with LMWH than with unfractionated heparin, LMWH is absolutely contraindicated in patients with a history of HIT because of the danger posed by this reaction.
A class I recommendation and level A evidence support the use of anticoagulation with intravenous heparin or subcutaneous LMWH in patients with unstable angina/NSTEMI; the anticoagulant is given in addition to aspirin, clopidogrel, or both. Level A evidence indicates that enoxaparin is preferable to unfractionated heparin in patients without renal failure, unless CABG is planned within 24 hours (class IIa recommendation).
Direct thrombin inhibitors
These agents directly bind to the fibrinogen-recognition and catalytic sites of thrombin, neutralize clot-bound thrombin, and inhibit thrombin-mediated platelet aggregation; the result is sustained anticoagulation. Hirudin and bivalirudin are the two principal agents that have undergone clinical testing, but hirudin is not used.
In the Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events-2 (REPLACE-2) trial, which involved patients undergoing percutaneous coronary intervention, bivalirudin in combination with provisional GPIIb-IIIa inhibition was found to be equivalent to unfractionated heparin plus GPIIb-IIIa inhibition in terms of death, MI, urgent repeat revascularization, and in-hospital major bleeding after 30 days of therapy.72 Rates of in-hospital major bleeding were significantly lower with bivalirudin (2.4% versus 4.1%; P < 0.001), although it has been noted that activated clotting time (ACT) values in the patients who received unfractionated heparin and a GpIIb-IIIa inhibitor were higher than was seen in other trials.
Bivalirudin is given as an intravenous bolus of 0.75 mg/kg at the start of percutaneous coronary intervention; for the duration of the procedure, an infusion of 1.75 mg/kg/hr is given. Because of the predictable profile of bivalirudin, measurement of ACT levels is usually not necessary. If the ACT is measured, typical values are 300 to 400 seconds.
Although bleeding seems to occur less commonly with bivalirudin than with unfractionated heparin or GPIIb-IIIa inhibitors, any serious bleeding that does occur could be disastrous because there is no effective way to immediately reverse the anticoagulation (as can be done with protamine sulfate for heparin). However, thrombocytopenia is not a problem, and the offset of bivalirudin's effect is relatively more rapid than that of heparin (1 hour), permitting sheaths to be pulled sooner after the procedure. Mainly because of its better safety profile, some interventional cardiologists have embraced the use of bivalirudin in the catheterization laboratory, but its general use awaits further trials.
If percutaneous coronary intervention is planned, level B evidence indicates that bivalirudin may be used as an alternative to unfractionated heparin and a GPIIb-IIIa inhibitor.
Warfarin
Warfarin works by inhibiting the vitamin K-dependent clotting factors II, VII, IX, and X. Achievement of the desired antithrombotic effect takes 4 to 7 days.
In a few small pilot studies, starting warfarin therapy shortly after presentation in patients with unstable angina/NSTEMI showed benefit.1 In a large trial of patients with unstable angina/NSTEMI who had previously undergone CABG, warfarin provided no advantage over aspirin alone and was associated with excess minor and major bleeding complications.73
Warfarin is taken orally once daily. The dose is titrated to maintain the desired international normalized ratio (INR), which is from 2 to 3 for most indications.
Bleeding is the main complication associated with warfarin therapy. Several drugs (e.g., cimetidine, amiodarone) can markedly increase warfarin's effect. Warfarin anticoagulation is reversed by stopping the drug; reversal by administration of vitamin K or of fresh frozen plasma is usually reserved for emergent and life-threatening bleeding.
The available evidence does not support the routine use of warfarin in patients with unstable angina/NSTEMI unless there are other indications for warfarin (e.g., atrial fibrillation, mechanical prosthetic heart valve).
Anti-ischemia Therapy
The agents used for treating ischemia in patients with unstable angina/NSTEMI include nitrates, morphine sulfate, and beta blockers (e.g., metoprolol) [see Table 6].
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Table 6 Anti-ischemia Therapy |
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Nitrates
Nitroglycerin is an endothelium-independent general arterial and venous dilator. It decreases myocardial oxygen demand through increased venous capacitance and peripheral artery dilation—factors that reduce preload and afterload, respectively, and thereby reduce myocardial wall stress. Epicardial coronary vasodilation and increased collateral flow act to enhance myocardial oxygen delivery.
No large, placebo-controlled clinical trials addressing reductions in major cardiac events or symptoms in unstable angina/NSTEMI have been performed. Multiple small, uncontrolled trials, a well-characterized biologic effect, and decades of experience have made nitrates a standard of care in the early treatment of these patients.1
In the emergency department, the initial nitrate dosage in a nonhypotensive patient is typically 0.4 mg of sublingual nitroglycerin (tablet or spray) repeated approximately every 5 minutes if ischemic symptoms do not subside. If this fails to terminate the ischemia, intravenous nitroglycerin at an infusion rate of 10 µg/min is recommended. The dose is titrated upward in increments of 10 to 20 µg/min until symptoms or signs of ischemia subside, hypotension develops, or the recommended maximal dose of 200 µg/min is achieved. After the acute period, topical nitrates, such as a 0.4 mg/hr nitrate patch, can be used for long-term therapy if necessary.
Nitroglycerin can result in significant hypotension, necessitating withdrawal of the agent. It should be avoided in patients who have taken sildenafil (Viagra) or vardenafil (Levitra) in the past 24 hours, because very severe hypotension can occur. Nitrate tolerance develops with prolonged nitrate administration, so patients should have nitrate-free intervals. Other adverse reactions, including intermittent headaches and nausea, are common.
A class I recommendation and level C evidence support the use of nitroglycerin to terminate or prevent ischemic episodes. Nitroglycerin therapy should serve as a bridge to the use of other evidence-based therapies, such as revascularization.
Morphine sulfate
Almost a century of experience in acute coronary syndrome (albeit in the absence of clinical trial data) has established morphine sulfate as a useful adjunct to the early management of unstable angina/NSTEMI. Besides its potent analgesic and anxiolytic effect, morphine sulfate causes venodilation and mild arterial dilation, leading to reduced preload and afterload, and it may increase vagal tone to modestly reduce heart rate. These effects make it useful for treating patients with severe pulmonary congestion.
Morphine sulfate is given in a dose of 1 to 5 mg intravenously every 10 to 15 minutes until ischemic symptoms dissipate. At the same time, consideration for intravenous nitroglycerin treatment should be made. Morphine sulfate often causes hypotension, nausea, vomiting, and respiratory depression. Effects are quickly reversible with naloxone. A class I recommendation and level C evidence support the use of morphine sulfate to relieve chest pain that is refractory to sublingual nitroglycerin, to reverse acute pulmonary edema, and to ease severe agitation.
Beta blockers
Beta blockers reduce myocardial oxygen demand by reducing heart rate and contractility. Slowing of the heart rate may also permit increased coronary filling during a prolonged diastole.
Much of the evidence in favor of beta-blocker therapy for unstable angina/NSTEMI is extrapolated from the large benefit shown in major clinical trials of acute MI. A meta-analysis of trials of threatened or evolving MI revealed a 13% reduction in progression to acute MI,74 but there was insufficient power for mortality analysis.
There is no evidence of any difference in efficacy between the various beta blockers available, although agents with intrinsic sympathomimetic activity should be avoided. The dose will vary with the agent selected. In unstable angina/NSTEMI, intravenous loading doses titrated to a target resting heart rate of 50 to 60 beats/min may be used, with rapid conversion to an oral regimen. In patients who may have difficulty tolerating the adverse effects of beta blockers, the initiating dose should be small and titration should proceed more slowly.
Bronchospasm and severe asthma are contraindications to the use of beta blockers. Significant sinus bradycardia, AV nodal block, and hypotension can also occur, typically in patients with preexisting disease of cardiac conductive tissue.
A class I recommendation and level B evidence support the use of beta blockers in patients with ongoing chest pain; in such patients, an initial intravenous dose is followed by oral therapy.
Calcium channel blockers
These agents are primarily vasodilators, but they also have effects on atrioventricular nodal conduction and left ventricular contractility. The dihydropyridine calcium channel blockers (e.g., nifedipine and amlodipine) have the most peripheral vasodilatory capability and the least negative inotropic effect.
To date, the trial data generally suggest that calcium channel blockers offer symptom relief in patients with unstable angina, but a meta-analysis found no improvements with regard to death or the occurrence of MI.75 Nifedipine, compared with a beta blocker (metoprolol), demonstrated a trend toward increased MI.76 In unstable angina/NSTEMI, the nondihydropyridine agents are used for coronary artery spasm and may be chosen for patients who cannot tolerate beta blockade.
Doses of calcium channel blockers vary with the agent chosen. For diltiazem, the usual immediate dose is a 20 mg/kg intravenous bolus, followed 15 minutes later by a 20 to 25 mg/kg bolus. Thereafter, the drug is administered orally, in a dosage of 30 mg three to four times a day, titrated to a total daily dose of 360 mg if necessary. Long-acting formulations exist as well.
Hypotension occurs with all calcium channel blockers. Bradycardia and negative inotropic effects accompany the nondihydropyridine agents; these agents should be avoided in patients with heart failure. The dihydropyridine agents may cause reflex tachycardia and other sympathomimetic effects.
Recommendations for the use of calcium channel blockers are as follows:
Lipid-Lowering Agents
There is as yet no evidence from a clinical trial that indicates that the use of lipid-lowering agents in hospital confers a benefit for patients with unstable angina/NSTEMI. However, data from a large Swedish registry showed a reduction in mortality in MI patients given statin therapy before discharge.77 In addition, patients given such therapy in the hospital are much more likely to continue it out of hospital, and in-hospital use has therefore been recommended.78,79 The use of a fibrate or niacin in patients with a high-density lipoprotein cholesterol level of less than 40 mg/dl is supported by a class I recommendation and level B evidence. A class IIa recommendation and level B evidence support treatment with statins and diet for patients whose low-density lipoprotein cholesterol is greater than 100 mg/dl; treatment should begin 24 to 96 hours after admission and continue after hospital discharge.
Angiotensin-Converting Enzyme Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors may block inflammatory processes and encourage plaque stability. In the Heart Outcomes Prevention Evaluation (HOPE) trial, use of the ACE inhibitor ramipril was associated with significant reductions in death, MI, or stroke in moderate- to high-risk patients, most of whom had normal left ventricular function.80 The American College of Cardiology/American Heart Association (ACC/AHA) recommends ACE inhibitors for patients with unstable angina/NSTEMI and heart failure; left ventricular systolic dysfunction (ejection fraction less than 40%); hypertension; or diabetes. This class I recommendation is supported by level B evidence.
MECHANICAL REVASCULARIZATION
Coronary revascularization with percutaneous procedures or CABG is performed to relieve symptoms and improve prognosis [see Early Invasive versus Conservative Strategy, above]. Several factors influence the decision to proceed with coronary revascularization, including risk, absence of relevant comorbid conditions, disabling symptoms, viable myocardium at risk, and whether the patient's coronary anatomy is suitable for the procedure.
Percutaneous Coronary Intervention
Advances in percutaneous coronary intervention techniques and devices have improved safety and long-term vessel patency rates. Several changes in the evolution of coronary stent design, including smaller profile, increased flexibility, small strut diameter, and, the newest development, drug-eluting technology, have improved deliverability and reduced the rate of instent restenosis. Furthermore, the use of adjunctive antiplatelet and antithrombotic therapies, particularly in the setting of acute coronary syndrome, has improved outcomes.
The ACC/AHA guidelines for the use or avoidance of percutaneous coronary intervention in unstable angina/NSTEMI are as follows1:
Surgical Revascularization
Surgical revascularization techniques and perioperative outcomes have improved over the years. Particular advances include use of internal mammary artery conduits, off-pump procedures, minithoracotomy, and, the newest development, robot-assisted procedures.
The ACC/AHA guidelines for CABG in patients with unstable angina/NSTEMI are as follows1:
Diabetes and Revascularization
Overall, patients with diabetes are more likely to require repeat revascularization after percutaneous intervention, because of increased rates of restenosis; in addition, there is a trend toward higher mortality 1 year after both CABG and percutaneous intervention with stents in diabetic patients.81 In the Bypass Angioplasty Revascularization Investigation (BARI) trial, diabetic patients with multivessel CAD were found to have better survival rates with CABG than with percutaneous intervention.82 However, analysis of the diabetic subgroup of a randomized trial and registry of percutaneous intervention with bare metal stents versus CABG in unstable angina patients revealed no difference in 3-year survival between the groups.83 Drug-eluting stents display markedly reduced rates of instent restenosis, as compared with traditional bare-metal stents, particularly in diabetic patients.84,85
Currently, the available evidence suggests that surgical revascularization should be offered to diabetic patients with CAD in three or more vessels, particularly if they have left ventricular dysfunction. However, it is common practice to offer percutaneous intervention as the revascularization strategy for diabetic patients with CAD involving one or two vessels. Trials are needed to compare the most advanced drug-eluting stent technology with the most advanced surgical management to define their roles in diabetic patients with CAD.
POSTHOSPITAL CARE
Preparation for the posthospital care of a patient with unstable angina/NSTEMI should begin during the hospitalization, with appropriate education, dietary advice, psychosocial counseling, weight loss advice, exercise prescription, cardiac rehabilitation referral (if appropriate), smoking cessation counseling, and the initiation of drug therapy. Given the importance of aggressive risk modification, the entire medical staff has a responsibility to ensure that all of these therapies and advice are offered, encouraged, and established for the future.78
Aspirin therapy should be maintained indefinitely, and clopidogrel should be taken for 9 months. For patients who have had an MI or who have left ventricular dysfunction, beta-blocker therapy is recommended indefinitely, in the absence of contraindications. ACE inhibitor treatment is recommended indefinitely for secondary prevention in moderate- to high-risk patients with atherosclerotic disease, diabetes, a low ejection fraction, or other specific indications. Lipid-lowering therapy (e.g., with a statin drug) should be administered if the patient has a low-density lipoprotein level higher than 100 mg/dl post diet (class I, level B), or a high-density lipoprotein level lower than 40 mg/dl (class IIa, level B).79 Blood pressure should be kept below 140/90 mm Hg unless the patient has renal disease or diabetes, in which case the target is a pressure lower than 130/80 mm Hg.86 All patients should be prescribed sublingual nitroglycerin and instructed in its use; in particular, they should understand the importance of returning to the hospital immediately if symptoms persist despite three doses of nitroglycerin. Finally, follow-up should take place 2 to 6 weeks after discharge in low-risk and revascularized patients, or 1 to 2 weeks after discharge in higher-risk patients.1
References
Editors: Dale, David C.; Federman, Daniel D.