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REVIEW DIAGNOSING ACUTE CORONARY SYNDROME AND DETERMINING PATIENT RISK — Edith A. Nutescu, PharmD* ABSTRACT Acute coronary syndrome is a form of coronary artery disease and has a broad range of clinical presentations. Generally, patients with acute coronary syndrome are categorized as having ST-segment elevation myocardial infarction, non–ST-segment elevation myocardial infarction, or unstable angina. The findings on the electrocardiogram and other information from a thorough history and clinical examination allow patients to be stratified according to their risk for further myocardial damage. Risk stratification will determine an individual patient’s need for aggressive cardiac treatment, observation, or referral. The clinical characteristics that can be used to determine a patient’s risk of death or a subsequent cardiac event are reviewed along with the American College of Cardiology/ American Heart Association guidelines for immediate management after risk stratification. (Adv Stud Pharm. 2006;3(3):106-111) *Clinical Associate Professor, Director, Antithrombosis Center, College of Pharmacy, The University of Illinois at Chicago, Chicago, Illinois. Address correspondence to: Edith A. Nutescu, PharmD, Clinical Associate Professor, Director, Antithrombosis Center, College of Pharmacy, The University of Illinois at Chicago, 833 South Wood Street, m/c 886, Room 164, Chicago, IL 60612. E-mail: [email protected]. 106 cute coronary syndrome (ACS) is a potentially life-threatening manifestation of coronary artery disease (CAD), which is the leading cause of death in the United 1 States. The term ACS describes a broad range of clinical presentations. Patients are generally categorized according to the results of an initial 12-lead electrocardiogram (ECG) as having ST-segment elevation myocardial infarction (STEMI) or non–ST-segment elevation myocardial infarction (NSTEMI). Patients with an initial ECG suggesting NSTEMI may be experiencing the closely related condition unstable angina (UA), which is a relatively high-risk intermediate state between stable angina and myocardial infarction. Both conditions are common manifestations of CAD that present as ACS.2 Persistent ST-segment elevation accompanied by chest pain usually indicates total coronary occlusion, resulting in irreversible myocardial damage. This presentation requires immediate reperfusion of the coronary vessel by medical or pharmacologic intervention to prevent further myocardial damage.3 Patients who present with chest pain but do not have persistent STsegment elevation are likely suffering from NSTEMI or UA, both of which are usually caused by partial occlusion of a coronary artery. In these patients, ischemia and symptoms should be relieved by appropriate pharmacologic therapy, such as aspirin, low–molecularweight heparin or unfractionated heparin, glycoprotein IIb/IIIa inhibitors, clopidogrel, beta blockers, nitrates, and statins. All patients should be subsequently monitored by serial ECGs and measurements of serum biomarkers for myocardial necrosis.3 Despite treatment advances, the rates of mortality, subsequent cardiac events, and hospitalization remain high for patients who present with ACS.1 The high rate of poor outcomes in these patients can be at least partially attributed to the overlapping characteristics of A Vol. 3, No. 3 n May 2006 REVIEW STEMI and NSTEMI/UA that complicate the diagnosis upon initial presentation.2 This article reviews the various clinical characteristics, the American College of Cardiology/American Heart Association (ACC/AHA) risk stratification guidelines for patients experiencing ACS, and treatment implications for patients with NSTEMI/UA. Table 1. Likelihood that Acute Coronary Syndrome Symptoms Result from Coronary Artery Disease High Risk Medium Risk Evaluation History Low Risk Findings • Chest discomfort or left arm pain • Recurrent, documented angina • History of coronary artery disease or myocardial infarction • Chest or left arm pain • Probable ischemic • Age >70 symptoms without • Male sex intermediate risk • Diabetes mellitus findings • Recent cocaine use CLINICAL EVALUATION Physical examination • New transient mitral Extracardiac vascular Chest discomfort on Typical symptoms of ACS regurgitation disease palpation include chest pain, referred • Hypotension • Diaphoresis pain, nausea, vomiting, dys• Pulmonary edema or pnea, diaphoresis, and lightrales headedness. Although some patients may not complain of ECG • New transient ST • Fixed Q waves • T-wave flattening chest pain, the presence of deviation • Pre-existing abnormal • T inversion in leads • T-wave inversion ST or T waves with dominant R symptoms such as referred pain with symptoms waves that radiates to the shoulder, left • Normal ECG results arm, or both arms increases the likelihood of ACS. Patients preSerum cardiac Elevated troponin T, Normal Normal senting with the 3 classic sympmarkers troponin I, or CK-MB toms of typical angina ECG = electrocardiogram; CK-MB= creatine kinase, myocardial bound. (substernal pain that occurs on Adapted with permission from Braunwald et al. Available at http:www.acc.org/clinical/guidelines/unstable/ exertion and is relieved by rest) unstable.pdf. Accessed March 25, 2006. have an increased risk of ACS.4 The presence of atypical symptoms does not rule out ACS. 2).2 The prognosis for patients with UA can be judged However, multiple atypical symptoms may be useful in 5 by the pace of their clinical course, which can predict identifying patients at low risk for ACS. their short-term risk for a cardiac event and their In patients presenting with chest pain, ruling out chance of surviving an event. Estimating risk for noncardiac causes is the primary challenge, requiring a patients with chest pain at rest can help the clinician thorough initial evaluation including history with risk determine the appropriate site of care and the approfactor analysis, physical examination, 12-lead ECG, priate therapy. Patients at the highest risk will likely and serum cardiac biomarker measurements, such as benefit from treatment in coronary care units, wherecardiac-specific troponins T and I.2 Table 1 lists the as patients at lesser risk may be appropriately managed clinical factors that characterize patients at high, mediin monitored step-down units or as outpatients. um, and low risk for ACS resulting from CAD. Likewise, risk stratification will identify those patients Patients with a history of ACS or persistent chest pain, who may benefit from more aggressive therapies, such unstable vital signs, and syncope should be considered as glycoprotein IIb/IIIa inhibitors.2 at the highest risk. For these patients, immediate transfer to a cardiac monitoring unit or emergency departDIAGNOSTIC ECG MORPHOLOGY ment is warranted.2 ST-ELEVATION MYOCARDIAL INFARCTION For patients who are diagnosed with UA, the shortAmong the clinical presentations of ACS, STEMI term risk of death or a cardiac event can be stratified is the most urgent because of the risk for progressive into high-, moderate-, and low-risk categories (Table 2 University of Tennessee Advanced Studies in Pharmacy n 107 REVIEW myocardial damage. Approximately 25% of patients with an ACS will present with new or presumed new ST elevation on their ECG.6 Normal or nondiagnostic ECGs do not preclude the presence or emergence of acute myocardial infarction (AMI). Therefore, ST deviation should be interpreted in the larger context of the clinical presentation and overall ECG characteristics.7 Because patients with STEMI are at high risk for progressive myocardial damage, they require immediate reperfusion therapy (either percutaneous coronary intervention or thrombolytic therapy) to open the occluded coronary artery.6 Table 2. Short-term Risk Stratification for Death or MI in Patients with Unstable Angina Feature High Risk Presence of ≥1 symptoms in this column, without high-risk features History Increasing ischemic symptoms in prior 48 hours Prior MI, peripheral or cerebrovascular disease, CABG, prior aspirin use Character of pain Prolonged ongoing (>20 minutes) rest pain ANGINA 108 •Resolved but prolonged (>20 minutes) rest angina with moderate or high likelihood of CAD Any symptom in this column without moderate- or highrisk features New-onset or progressive CCS Class III or IV angina in the past 2 weeks without prolonged (>20 minutes) rest pain but with moderate or high likelihood of CAD •Rest angina (<20 minutes) or relieved with rest or sublingual nitroglycerin INFARCTION AND UNSTABLE DIAGNOSTIC SERUM CARDIAC MARKERS Table 3 summarizes the important clinical points for 3 serum cardiac markers that are crucial for distinguishing Low Risk Presence of ≥1 symptoms in this column NON–ST-ELEVATION MYOCARDIAL Approximately 75% of patients with an ACS present with NSTEMI or UA. Of these patients, 40% to 60% will be diagnosed with NSTEMI based on positive cardiac troponins, and the rest will have UA. ECG changes associated with NSTEMI/UA may include such changes as ST depression or other ST-segment abnormalities, T-wave inversion, or the ECG may be normal. ST depression is associated with increased mortality, especially when present in ≥2 ECG leads.8 Primary ST depression is not an indication for thrombolytic therapy. Moderate Risk Clinical findings •Pulmonary edema, Age >70 years likely from ischemia •New or worsening mitral regurgitation murmur •S3 or new worsening rales •Hypotension, bradycardia, tachycardia •Age >75 years ECG •Angina at rest with transient ST-segment changes >0.05 mV •Bundle-branch block, new or presumed new •Sustained ventricular tachycardia Cardiac markers Elevated troponin T or I (>0.1 ng/mL) •T-wave inversions >0.2 mV •Pathological Q waves Slightly elevated troponin T or I (<0.1 ng/mL) Normal or unchanged ECG during an episode of chest discomfort Normal MI = myocardial infarction; CABG = coronary artery bypass graft; CAD = coronary artery disease; ECG = electrocardiogram. Adapted with permission from Braunwald et al. Available at http:www.acc.org/clinical/guidelines/unstable/ unstable.pdf. Accessed March 25, 2006.2 Vol. 3, No. 3 n May 2006 REVIEW NSTEMI from UA. Creatine kinase Table 3. Serum Cardiac Markers for Acute Myocardial Infarction (CK) is an enzyme found in many body organs and striated muscle. CK *Positive *Negative may be elevated in cardiac and noncarHours to First Hours to Peak Predictive Predictive diac conditions; therefore, it is sensitive Protein Marker Positive Test Level Value % Value % or specific for detecting myocardial Creatine kinase 3–8 12–24 30 99 injury.4 The more cardiac-specific CK Creatine kinase-MB 4–6 12–24 73 99 isoenzyme CK-MB replaced CK testTroponin I and T 4–10 8–28 72 98 ing, but because it is also found in skeletal muscle and the blood of *Measured by serial assays Adapted with permission from Achar et al. Am Fam Physician. 2005;72(1):119-126. healthy patients, it also lacks sensitivity for detecting cardiac necrosis. CK-MB is helpful in the early diagnosis of AMI because CK-MB is typically detectable in the blood earlier than other cardiac markers.2 Although CK-MB isoform risk of poor outcomes in patients with ACS.2 Further assays are not yet widely available, 1 large study sugresearch is needed to determine whether these markers gested that CK-MB isoform analysis has sensitivity will have utility in risk stratification algorithms. and specificity of approximately 95% six hours after symptom onset.9 RISK STRATIFICATION AND TREATMENT IMPLICATIONS The isoforms of cardiac troponins, troponin T and Patient history, physical examination, and laboratroponin I, are specific to cardiac muscle and, theretory assessment are key for detecting the presence of fore, are the most reliable indicators of cardiac damcardiovascular disease risk factors. The degree of carage.10 Because of their high sensitivity and specificity diovascular risk attributable to these risk factors is profor even small amounts of myocardial injury, the ACC portional to their severity and duration. Because the and the European Society of Cardiology now recomincidence of cardiac events increases with age, is highmend the use of cardiac troponins as the preferred bioer in men than in women (and affects men at an earlimarker for diagnosing MI.3 The presence of normal er age), and is higher in people with a family history of CK-MB and elevated cardiac troponins typically indiheart disease, the AHA has identified age, male sex, cates minor myocardial damage or microinfarction. and heredity as the major nonmodifiable cardiovascuHowever, elevation in both of these markers indicates lar risk factors. Similarly, the AHA has identified AMI.4 The level of serum troponins correlates with the smoking, high cholesterol, hypertension, physical risk of death and subsequent cardiac events. Patients inactivity, excess body fat, and diabetes as the major with high troponin levels will require the most urgent modifiable risk factors for coronary disease.14 The presintervention, whereas patients with low troponin levence of traditional risk factors should be taken into els may be monitored as outpatients.11,12 In patients account when determining the prognosis of patients with negative cardiac markers collected within 6 hours who present with ACS. of chest pain onset, another sample should be analyzed The estimation of risk level for patients with ACS over the next 8 to 24 hours. depends on multiple variables and cannot be reduced Elevated levels of other biochemical markers, such to a simple algorithm. Nevertheless, an assessment of as highly sensitive C-reactive protein (hs-CRP) and prognosis often determines the pace of initial evaluafibrinogen, have been observed in patients with tion and treatment strategies. There is a strong relaischemic chest pain.13 Although data supporting the tionship between ischemia caused by CAD and poor routine measurement of these markers are unavailable, prognosis. Therefore, determining the likelihood of they may provide supportive diagnostic information. CAD will aid in estimating prognosis in addition to Elevated fibrinogen, for example, indicates coagulaselecting the site of care and initial therapy.2 As a clintion cascade activity and is associated with increased ical presentation, NSTEMI/UA shares characteristics risk for poor outcomes in patients with ACS.2 with several lower and higher risk conditions, such as Similarly, elevated hs-CRP is associated with increased severe chronic stable angina and STEMI. 4 University of Tennessee Advanced Studies in Pharmacy n 109 REVIEW The Thrombolysis in Myocardial Infarction (TIMI) risk score is a validated, arithmetic tool to predict a patient’s risk of death and cardiac ischemic events when they present with NSTEMI/UA.2 The TIMI risk score is calculated from the sum of variables that are easily attained during the initial evaluation (Table 4). Using the TIMI score system, Antman et al showed that as the TIMI score increased in the study population, the risk of death, MI, or recurrent ischemia requiring urgent revascularization increased significantly (Figure).15 Patients with the lowest scores upon presentation were at nearly 5% risk for reaching the composite endpoint (ie, death, new or recurrent MI, or revascularization), whereas patients with the highest number of factors upon presentation were at nearly 41% risk for the endpoint. The TIMI risk score can guide clinicians as they plan further evaluations and treatment by providing a reliable prognostic assessment for individual patients. Patients at progressively higher risk have been shown to benefit from newer therapies, such as low–molecular-weight heparin or glycoprotein IIb/IIIa inhibitors, in addition to an early invasive strategy, such as percutaneous coronary intervention.16-18 Therefore, the TIMI risk score may be useful in identifying patients who would benefit from these newer therapies.2 The use of the TIMI risk score, in combination with the information gathered from the physical examination, medical history, ECG, and cardiac biomarkers, can be used to assess the risk of mortality and other major adverse cardiac events. Such a risk assessment can then be used to determine the aggressiveness of evaluation and therapy. In addition to appropriate pharmacological therapy, patients at higher risk are typically treated with an early invasive approach consisting of coronary angiography followed by percutaneous coronary intervention, if appropriate.2 A less aggressive approach is often appropriate in patients deemed to be at lower risk. CONCLUSIONS In patients with chest pain, differentiating between cardiac and noncardiac causes represents a major challenge. Similarly, determining the immediate risk for patients with ACS requires a thorough clinical evaluation. Patients with ST elevation on their initial ECGs are at significant risk of progressive myocardial damage and require urgent revascularization. For patients who do not have ST elevation, other factors, such as medical history, physical examination, and cardiac biomarkers, 110 Table 4. TIMI Risk Score for NSTEMI/UA Factor Point Value Age >65 ≥3 CAD risk factors Prior coronary stenosis =50% ST deviation at presentation ≥2 anginal events in past 24 hours Aspirin use in prior 7 days Elevated serum cardiac markers 1 1 1 1 1 1 1 Total of 7 TIMI = Thrombolysis in Myocardial Infarction; NSTEMI/UA = non–ST-segment elevation myocardial infarction/unstable angina; CAD= coronary artery disease. Adapted with permission from Antman et al. JAMA. 2000;284(7):835-842.15 Figure. TIMI Risk for Death, MI, or Urgent Revascularization TIMI= Thrombolysis in Myocardial Infarction; MI= myocardial infarction. P <.001 for trend. Adapted with permission from Antman et al. JAMA.2000;284:835-842.15 are used to help identify those patients at higher risk who are likely to benefit from aggressive therapies. The cardiac troponins T and I are the gold standard for determining the presence and extent of myocardial damage. A risk stratification method that uses easily obtained information, such as the TIMI risk score, can help identify those patients who are at the greatest risk for poor outcomes. Therefore, risk stratification is essential to determining an appropriate management strategy and may prove to be a factor in reducing the high rates of mortality associated with ACS. Vol. 3, No. 3 n May 2006 REVIEW REFERENCES 1. Thom T, Haase N, Rosamond W, et al. Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2006;113(6):85-151. 2. Braunwald E, Antman E, Beasley J, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. Available at: http://www.acc.org/ clinical/guidelines/ unstable/unstable.pdf. 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