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Unstable Angina and NSTEMI: Are You Up to Date?
The latest guidelines for managing unstable angina and non-ST-segment-elevation myocardial infarction underscore the critical role emergency physicians play in prompt recognition and treatment of these conditions.
By Michael C. Cunningham, MD, John P. Reilly, MD, Carl J. Lavie, MD, and Erik T. Sundell, MD
Coronary heart disease (CHD) is the leading cause of death in the United States, and unstable angina (UA) and non-ST-segment-elevation myocardial infarction (NSTEMI) are often acute manifestations of this disease. Each year, UA and NSTEMI affect more than 1.2 million people in this country, causing significant morbidity and mortality.
In 2007, the American College of Cardiology (ACC) and American Heart Association (AHA) released updated guidelines for the management of patients with UA and NSTEMI, revised from previous guidelines due to a growing body of evidence from clinical trials. The new guidelines were developed by experts from the ACC and the AHA, in collaboration with the American College of Emergency Physicians. The writing committee performed a literature review and made recommendations based on the strength of existing evidence. The committee created classifications (classes I, IIa, IIb, and III) and levels of evidence for each recommendation in order to estimate both the size and certainty of an effect for each recommendation.
These new guidelines reinforce that correct management of UA and NSTEMI depends largely on prompt recognition and treatment in the emergency department. This article will provide an overview of the 2007 guidelines as they apply to emergency physicians, including new recommendations, the importance of early identification, and proper management of UA and NSTEMI.
MANIFESTATIONS OF ACUTE CORONARY SYNDROME
Acute coronary syndrome (ACS) is a catch-all term used to indicate a patient with myocardial ischemia or injury. There are three manifestations of ACS: ST-elevation MI (STEMI), UA, and NSTEMI. All of these patients are characterized by myocardial supply-demand mismatch.
The cause of STEMI is usually acute atherosclerotic plaque rupture with occlusive thrombus formation. This type of MI has distinct ECG abnormalities and is best treated emergently with thrombolytics or percutaneous coronary intervention. Unstable angina is characterized by new-onset angina (within one month), angina at rest, or a change in anginal pattern from baseline. It may be associated with ECG changes. Abnormal cardiac enzymes distinguish NSTEMI from UA. These two diagnoses represent a spectrum of the same pathophysiologic process rather than two distinct diseases.
The most common cause of UA and NSTEMI is progressive atherosclerotic disease of the coronary arteries resulting in narrowing and eventual thrombosis with near-occlusion or occlusion of the culprit vessel. However, other causes do occur, and more than one may be present simultaneously (see box above).
INITIAL EVALUATION AND MANAGEMENT
Patients with symptoms of ACS should never be evaluated over the telephone. Studies have shown that, on average, UA and NSTEMI patients do not seek care until two hours after symptom onset. The revised guidelines emphasize reducing this delay and also include recommendations for educating patients on the signs and symptoms of ACS and what to do if they occur for the first time. For example, patients who are prescribed nitroglycerin are advised to contact EMS if their symptoms are not relieved or if they worsen after taking one sublingual nitroglycerin tablet. Previous recommendations were to take up to three tablets before notifying EMS. If symptoms do improve, taking up to three nitroglycerin tablets before notifying EMS is still considered appropriate. Likewise, the guidelines encourage early aspirin use when no contraindications exist, with aspirin being self-administered by the patient, administered by EMS, or taken immediately on arrival in the emergency department. In addition, 911 dispatchers may advise patients to take both nitroglycerin and aspirin before EMS arrival—a new class IIa recommendation.
Initial risk assessment strategies have changed very little from 2002. Early risk stratification is critical, and it is especially important not to overlook noncoronary causes of the patient’s symptoms and to continue to evaluate these nonischemic symptoms in patients at low risk for CHD. Life-threatening conditions, such as aortic dissection and pulmonary embolus, should always be considered when evaluating for ACS, and a quick assessment should be done of the likelihood for CHD and the risk of a cardiovascular event.
Several options are available to assess this risk, but the thrombolysis in MI risk score is probably the best known and easiest to use (see graph below). This score identifies higher risk based on seven variables and helps target patients who need more aggressive therapy.
Electrocardiogram evaluation within 10 minutes is necessary to rapidly assess for acute injury or ischemia. In addition, a new class I recommendation is to perform serial 12-lead ECGs every 15 to 30 minutes in patients who continue to have ACS symptoms and who have a high clinical suspicion of ACS (continuous 12-lead monitoring is a class IIa alternative to serial ECGs). Another new class IIa recommendation is to obtain V7 to V9 leads to rule out a posterior MI in patients with an initial nondiagnostic ECG. This test is an easy way to diagnose a left circumflex occlusion that necessitates emergent reperfusion, but it is often not performed in patients who have persistent symptoms of ACS.
The guidelines show that biomarkers continue to be extremely important for risk assessment. Troponin (T or I) is now the preferred biomarker for assessing myocardial injury and the only biomarker with a class I indication. Myoglobin measurement has been downgraded to a class IIb when ruling out MI in patients presenting with possible ACS less than six hours from symptom onset. This is because the specificity for a myocardial event is low and myoglobin is elevated in a large number of emergency department patients. However, the guidelines introduced a new class IIb recommendation: two-hour delta-creatinine kinase myocardial band (CK-MB) measurements and two-hour delta-troponin measurements in patients presenting within six hours with normal biomarker levels. This method analyzes for a trend or increase in the biomarker level while it is still in the normal range. This may allow patients who present with ACS symptoms early to be identified more quickly so aggressive therapy can be initiated sooner.
B-type natriuretic peptide (BNP) is another biomarker new to the guidelines. Although atypical of the traditional biomarkers that are released only when myocardial necrosis occurs, BNP has been shown to predict short- and long-term mortality in UA and NSTEMI and is therefore useful in assessing the patient’s overall risk.
DOMINANT BIOMARKER
As mentioned previously, troponin has become the dominant biomarker. There are several reasons for this. It has short- and long-term prognostic implications that are incremental to other prognostic findings. It may become elevated as early as two hours after symptoms begin, but it typically becomes abnormal at four to six hours, and its long half-life allows detection of myocardial necrosis up to several days post event. Troponin is more sensitive than other assays in assessing for myocardial necrosis, so it allows practitioners to identify high-risk patients who require more aggressive therapy.
Importantly, 30% to 40% of NSTEMI patients would be classified as UA if CK-MB were the only biomarker tested. However, physicians should be familiar with the specific test their laboratory performs, because several tests are being used with many different normal ranges. They should also be aware that troponin T is less specific in the setting of renal dysfunction, resulting in more false positives; however it still retains prognostic value.
After risk stratification with the history, physical examination, biomarkers, and ECG, the patient should be placed in a clinical category so he can be managed appropriately. These categories include noncardiac diagnosis, chronic stable angina, possible ACS, and definite ACS. Patients with a noncardiac diagnosis should be treated appropriately. Chronic stable angina is rarely encountered in the emergency department, but if it is, the patient should be treated according to guidelines for that problem. Possible ACS patients should be observed with cardiac monitoring and additional biomarker measurements at appropriate intervals in either a chest pain center or telemetry unit. Those whose workups remain negative should receive a predischarge stress test.
An alternative for patients whose biomarkers remain negative after 12 hours of observation is discharge on appropriate pharmacotherapy (aspirin, sublingual nitroglycerin, and beta blockers) with a stress test within 72 hours. A pharmacologic stress test is a reasonable alternative in patients unable to exercise. Computed angiography is an alternative (class IIa) to stress testing in low- to intermediate-risk patients with normal cardiac workups. Patients whose noninvasive studies are normal need reassurance and outpatient follow-up. Those with abnormal stress tests or positive computed angiographies should be admitted to the hospital and treated for probable or definite ACS.
Patients who definitely have ACS should be admitted to the hospital after the need for emergent reperfusion therapy is ruled out with an ECG. Patients with ongoing symptoms or hemodynamic/electrical instability should be placed in a coronary care unit; most other patients can be monitored on a telemetry unit.
EARLY HOSPITAL CARE
The early hospital care portion of the guidelines contains numerous changes. This section is important to review because many emergency physicians also staff chest pain centers and provide care for patients beyond the initial history, physical, and immediate management. Ideally, many of the recommended therapies will be initiated in the emergency department.
The guidelines for anti-ischemic therapy underwent major revisions. Guidelines for using supplemental oxygen and nitroglycerin remain unchanged and still receive class I recommendations for hypoxemia and symptoms, respectively. The principal change in this section involves beta blocker administration and is due in large part to results of the COMMIT study, a randomized trial of more than 45,000 Chinese patients with STEMI (93%) or NSTEMI (7%). No significant clinical benefit was seen when these patients were given early aggressive intravenous beta blocker therapy. After 28 days, there was no difference in the composite end point of death, reinfarction, or cardiac arrest compared with a placebo. In fact, an increase in the incidence of cardiogenic shock offset a small to moderate decrease in reinfarction and ventricular fibrillation. This was especially prominent in hemodynamically unstable patients. As a result, the guidelines state that intravenous beta blockers should not be administered routinely and should only be used for specific indications, such as hypertension, where they receive a class IIa recommendation.
In contrast, oral beta blockers continue to receive a class I indication and should be initiated within 24 hours, but only for patients without contraindications (see box below). If contraindications such as left ventricular dysfunction are present initially, the guidelines recommend reevaluating the patient’s candidacy for oral beta blockers every 24 hours. In patients without contraindications who are intolerant of beta blockers and have persistent or recurrent ischemia, a non-dihydropyridine calcium channel blocker, such as verapamil or diltiazem, should be administered.
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Sublingual nitroglycerin also continues to receive a class I indication for persistent ischemia, and intravenous nitroglycerin should be administered if needed for persistent ischemia, hypertension, or congestive heart failure that occurs in the initial 48 hours of care. However, administration of intravenous nitroglycerin should not preclude the use of oral beta blockers or angiotensin-converting enzyme inhibitors, which have proven mortality benefits. In situations where ischemic symptoms persist despite maximal pharmacologic management, morphine sulfate is downgraded to a class IIa recommendation due to a possible increase in mortality.
ANTIPLATELET THERAPY
Guidelines for antiplatelet therapy underwent major changes in the 2007 revision with an emphasis on more aggressive and earlier (or “upstream”) delivery of antiplatelet agents. However, aspirin therapy recommendations are largely unchanged. In the absence of contraindications, the initial dose of aspirin is 162 to 325 mg, followed by 75 to 162 mg daily for life. Because they are absorbed more rapidly, nonenteric-coated formulations are preferred. Thienopyridines such as clopidogrel or ticlopidine, which exert their effect by inhibition of adenosine diphosphate receptors, should be given instead of aspirin if a contraindication to aspirin exists. Clopidogrel, rather than ticlopidine, has become the agent of choice due to equivalent efficacy, fewer side effects, and once-daily dosing. The guidelines now recommend administering a loading dose for these drugs, not simply initiating daily therapy. Patients on clopidogrel should receive a 300-mg loading dose, with an option for 600 mg, followed by 75 mg once daily. Although the 600-mg loading dose is not approved by the FDA, it has shown superior outcomes in small trials, produces greater maximal platelet inhibition and more rapid platelet inhibition (usually within two hours), and may decrease the chance of clopidogrel resistance.
In our emergency department, we routinely give a 600-mg loading dose of clopidogrel to patients with ACS once the decision to start dual antiplatelet therapy is made. The consensus is to give patients both aspirin and clopidogrel regardless of whether an invasive or conservative strategy is chosen, as long as the likelihood of bypass surgery is low. Because of the chance of bleeding complications in patients who proceed to surgery, emergency physicians, cardiologists, and cardiothoracic surgeons should collaborate on a protocol to determine who will receive dual antiplatelet therapy as initial therapy. Due to the elevated bleeding risk from antiplatelet medications, it is now recommended that patients on aspirin or a thienopyridene, or both, should receive gastrointestinal prophylaxis to minimize the risk of bleeding if they have a history of gastrointestinal bleeding.
Upstream glycoprotein (GP) IIb/IIIa inhibitors are recommended for most high-risk patients and those with elevated troponin if an invasive strategy is chosen. Ideally, these medications are initiated in the emergency department. Even with clopidogrel pretreatment, patients with elevated troponin appear to receive additional benefit from GP IIb/IIIa inhibitors. Eptifibatide and tirofiban are preferred for upstream use, but abciximab can be used if minimal or no delay to catheterization is expected. Thus, it is important to know whether the patient will proceed to an early invasive strategy before considering the use of these medications.
The recommendations for enoxaparin and unfractionated heparin remain largely unchanged in the guidelines, but other options for anticoagulation emerge for the first time. Most of the changes in anticoagulation recommendations are the result of the OASIS-5 and ACUITY trials. As a result, the antithrombin agents bivalirudin and fondaparinux make their debut in these guidelines as options for anticoagulation. The ACUITY study showed that in patients with NSTEMI and UA who were treated with an early invasive strategy, bivalirudin alone was not inferior to heparin plus a GP IIb/IIIa inhibitor in the composite ischemic endpoint. Moreover, it significantly reduced bleeding rates at 30 days. Similarly, the OASIS-5 trial confirmed that fondaparinux was not inferior to enoxaparin in reduction of the composite endpoint (death, MI, refractory ischemia at nine days) and reduced major bleeding events.
Consequently, both bivalirudin and fondaparinux have class I recommendations, but bivalirudin should only be used in patients who are managed with an initial invasive strategy. Fondaparinux can be used with either management approach and is the preferred agent for conservatively managed patients at higher risk for bleeding events. However, fondaparinux is associated with catheter-related thrombosis during percutaneous intervention, and some physicians still have concerns about its use in patients treated invasively. Additionally, clopidogrel is recommended if bivalirudin is selected and a GP IIb/IIIa inhibitor is not used intravenously. However, in the ACUITY trial, mortality and bleeding events were similar regardless of clopidogrel preloading. As with dual- and triple-antiplatelet therapy, given concerns for procedural hemorrhage, a multidisciplinary approach should be taken that includes cardiologists and emergency physicians to ascertain the appropriate protocol. If no protocol exists, the admitting physician should be consulted regarding appropriate therapy.
The remainder of the guidelines mainly focus on the selection of a conservative versus early invasive strategy. Revascularization strategies, late hospital care, discharge, and post-discharge care are also discussed at length but are beyond the scope of this article. We recommend reviewing the entire document for full details of these sections.
EXTENSIVE REVISIONS
Guideline revisions published in 2007 were extensive in many areas. For example, emphasis was placed on reducing the time from symptom onset to health care provider contact, troponin was stressed as the biomarker of choice, more aggressive antiplatelet strategies were recommended, and more anticoagulation options were offered. We hope this review will serve as a useful reference for emergency physicians and all health care providers who evaluate and manage UA/NSTEMI patients.
Suggested Reading
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Galvani M, et al.: N-terminal pro-brain natriuretic peptide on admission has prognostic value across the whole spectrum of acute coronary syndromes. Circulation 110(2):128, 2004.
Hochholzer W, et al.: Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 111(20):2560, 2005.
Kastrati A, et al.: Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. JAMA 295(13):1531, 2006.
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Rosamond W, et al.: Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 115(5):e69, 2007.
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von Beckerath N, et al.: Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 112(19):2946, 2005.
Young GP, et al.: Serial creatine kinase-MB results are a sensitive indicator of acute myocardial infarction in chest pain patients with nondiagnostic electrocardiograms: the second Emergency Medicine Cardiac Research Group Study. Acad Emerg Med 4(9):869, 1997.
Yusuf S, et al.: Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 354(14):1464, 2006.
Zipes DP and Braunwald E: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 7th ed. WB Saunders, 2005, pp. xxi, 2183, 75. |
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