Summary of Recommendations for Prognosis: Early Risk Stratification Recommendations COR LOE References Perform rapid determination of likelihood of ACS, including a 12-lead ECG within 10 min of arrival at an emergency facility, in patients whose symptoms suggest ACS I C 21 Perform serial ECGs at 15- to 30-min intervals during the first hour in symptomatic patients with initial nondiagnostic ECG I C N/A Measure cardiac troponin (cTnI or cTnT) in all patients with symptoms consistent with ACS* I A 21, 64, 67 71 Measure serial cardiac troponin I or T at presentation and 3 6 h after symptom onset* in all patients with symptoms consistent with ACS Use risk scores to assess prognosis in patients with NSTE-ACS I A 42 44, 75 80 Risk-stratification models can be useful in management IIa B 42 44, 75 81 Obtain supplemental electrocardiographic leads V7 in patients with initial nondiagnostic ECG at intermediate/high risk for ACS IIa B 82 84 Continuous monitoring with 12-lead ECG may be a reasonable alternative with initial nondiagnostic ECG in patients at intermediate/high risk for ACS BNP or NT pro-BNP may be considered to assess risk in patients with suspected ACS IIb B 87 91 *See Section 3.4, Class I, #3 recommendation if time of symptom onset is unclear. ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; COR, Class of Recommendation; cTnI, cardiac troponin I; cTnT, cardiac troponin T; ECG, electrocardiogram; LOE, Level of Evidence; N/A, not available; NSTE-ACS, non ST-elevation acute coronary syndromes; and NT pro-BNP, N-terminal pro- B-type natriuretic peptide. Figure 2. Global Registry of Acute Coronary Events Risk Calculator for In-Hospital Mortality for Acute Coronary Syndrome. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e357 are less helpful, although by suggesting prior MI, they indi- cate a high likelihood of significant CAD. Isolated Q waves in lead 3 are a normal finding. A completely normal ECG in a patient with chest pain does not exclude ACS, because 1% to 6% of such patients will have a MI, and at least 4% will have Fibrinolytic therapy is contraindicated for patients with ACS without ST-elevation, except for those with electro- cardiographic evidence of true posterior MI (ie, ST-elevation in posterior chest leads [V7 ]). This can be evaluated when acute myocardial infarction (AMI) is suspected but electrocardiographic changes are modest or not present82 84 ; a transthoracic echocardiogram to evaluate for posterior wall motion abnormalities may also be helpful in this setting. Alternative causes of ST-T changes include LV aneurysm, pericarditis, myocarditis, bundle-branch block, LV hypertro- phy, hyperkalemia, Prinzmetal angina, early repolarization, apical LV ballooning syndrome (Takotsubo cardiomyopathy, Section 7.13), andWolff-Parkinson-White conduction. Central nervous system events and therapy with tricyclic antidepres- sants or phenothiazines can cause deep T-wave inversion. 3.3.2.5. Physical Examination The physical examination is helpful in assessing the hemodynamic impact of an ischemic event. Patients with suspected ACS should have vital signs measured (BP in both arms if dissection is sus- pected)andshouldundergoathoroughcardiovascularexamination. Patients with evidence of LV dysfunction on examination (eg, rales, gallop) or acute mitral regurgitation have a higher likelihood of severe underlying CAD and are at high risk of a poor outcome. In the SHOCK (Should we Emergently Revascularize Occluded Coronaries for Cardiogenic Shock) study, NSTEMI accounted for Other trials have reported lower percentages.92,151 The physical examina- tion may also help identify comorbid conditions (eg, occult GI bleeding) that could impact therapeutic risk and decision making. See Online Data Supplement 2 for additional information on risk stratification. 3.4. Cardiac Biomarkers and the Universal Definition of MI: Recommendations See Table 5 for a summary of recommendations from this sec- tion and Online Data Supplement 3 for additional information on cardiac injury markers and the universal definition of AMI. 3.4.1. Biomarkers: Diagnosis Class I 1. Cardiac-specific troponin (troponin I or T when a contemporary assay is used) levels should be mea- sured at presentation and 3 to 6 hours after symp- tom onset in all patients who present with symptoms consistent with ACS to identify a rising and/or falling (Level of Evidence: A) 2. Additional troponin levels should be obtained beyond 6 hours after symptom onset in patients with normal troponins on serial examination when electrocardio- graphic changes and/or clinical presentation con- fer an intermediate or high index of suspicion for (Level of Evidence: A) 3. If the time of symptom onset is ambiguous, the time of presentation should be considered the time of onset for assessing troponin values.67,68,72 (Level of Evidence: A) Class III: No Benefit 1. With contemporary troponin assays, creatine kinase myocardial isoenzyme (CK-MB) and myoglobin are not useful for diagnosis of ACS.158 164 (Level of Evidence: A) 3.4.2. Biomarkers: Prognosis Class I 1. The presence and magnitude of troponin elevations are useful for short- and long-term prognosis.71,73,165,166 (Level of Evidence: B) Class IIb 1. It may be reasonable to remeasure troponin once on day 3 or day 4 in patients with MI as an index of infarct size and dynamics of necrosis.164,165 (Level of Evidence: B) 2. Use of selected newer biomarkers, especially B-type natriuretic peptide, may be reasonable to provide additional prognostic information.87,88,167 171 (Level of Evidence: B) Cardiac troponins are the mainstay for diagnosis of ACS and for risk stratification in patients with ACS. The primary diagnostic biomarkers of myocardial necrosis are cardiac troponin I and cardiac troponin T. Features that favor troponins for detection of ACS include high concentrations of troponins in the myo- cardium; virtual absence of troponins in nonmyocardial tissue; high-release ratio into the systemic circulation (amount found in blood relative to amount depleted from myocardium); rapid release into the blood in proportion to the extent of myocardial injury; and the ability to quantify values with reproducible, inexpensive, rapid, and easily applied assays. The 2012 Third Universal Definition of MI provides criteria that classify 5 clini- cal presentations of MI on the basis of pathological, clinical, and prognostic factors.21 In the appropriate clinical context, MI is indicated by a rising and/or falling pattern of troponin with 1 value above the 99th percentile of the upper reference level and evidence for serial increases or decreases in the levels of The potential consequences of emerging high- sensitivity troponin assays include increases in the diagnosis of influenced by the definition of an abnormal tro- The recommendations in this section are formu- lated from studies predicated on both the new European Society of Cardiology/ACC/AHA/World Health Organization criteria21 and previous criteria/ redefinitions of MI based on earlier-gener- ation troponin assays (Appendix 4, Table A). 3.4.3. Cardiac Troponins See Online Data Supplement 4 for additional information on cardiac troponins. Of the 3 troponin subunits, 2 subunits (troponin I and troponinT) are derived from genes specifically expressed in the myocardium. Cardiac troponin measurements provide highly sensitive results specific for detecting cardiomyocyte necrosis.34,173 Highly sensitive assays can identify cardiac troponin not only in the blood of patients with acute cardiac injury, but also in the blood of most healthy peo- As assay sensitivity increases, a greater proportion of patients will have detectable long-term elevations in troponin, thus requiring consideration of serial changes for the diagnosis of MI.Cliniciansshouldbeawareofthesensitivityofthetestsusedfor troponin evaluation in their hospitals and cutpoint concentrations for clinical decisions. Markedly elevated values are usually related to MI, myocarditis, rare analytical factors, or chronic elevations in patients with renal failure and in some patients with HF. CPGs endorse the 99th percentile of the upper reference level as the appropriate cutpoint for considering myocardial For the diagnosis of acute myocardial necrosis, it is important to determine not only the peak troponin value, but also serial changes: 1. A troponin value above the 99th percentile of the upper reference level is required. Additionally, evidence for a serial increase or decrease 20% is required if the initial value is elevated.21,178 2. For any troponin values below or close to the 99th percentile, evidence for acute myocardial necrosis is indicated by a change of 3 standard deviations of the variation around the initial value as determined by the 3. Clinical laboratory reports should indicate whether sig- nificant changes in cardiac troponin values for the par- ticular assay have occurred. Absolute changes in nanograms per liter of high-sensitivity cardiac troponin T levels appear to have a significantly higher diagnostic accuracy for AMI than relative changes and may distinguish AMI from other causes of high-sensitivity cardiac troponin T elevations.71 This has also been suggested for some Troponins are elevated in MI as early as and many medical centers obtain troponins at 3 hours. Depending on the assay, values may not become abnormal for up to 12 hours. In the vast majority of patients with symptoms suggestive ofACS, MI can be excluded or confirmed within 6 hours, because very few patients present immediately after symptom onset. In high-risk patients, mea- surements after 6 hours may be required to identify ACS. Solitary elevations of troponin cannot be assumed to be due to MI, because troponin elevations can be due to tachyarrhyth- mia, hypotension or hypertension, cardiac trauma, acute HF, myocarditis and pericarditis, acute pulmonary thromboembolic disease, and severe noncardiac conditions such as sepsis, burns, respiratory failure, acute neurological diseases, and drug toxicity (including cancer chemotherapy). Chronic elevations can result from structural cardiac abnormalities such as LV hypertrophy or ventricular dilatation and are also common in patients with renal Patients with end-stage renal disease and no clini- cal evidence of ACS frequently have elevations of cardiac tropo- With conventional assays, this is more common with cardiac troponin T than with cardiac troponin I.180 In the diagnosis of NSTEMI, cardiac troponin values must manifest an acute pat- tern consistent with the clinical events, including ischemic symp- toms and electrocardiographic changes. Troponin elevations may persist for up to 14 days or occasionally longer. There is a paucity of guidelines for establishment of reinfarction during the acute infarct period on the basis of troponin measurements. References suggest that an increase of >20% of previous troponin levels or an absolute increase of high-sensitivity cardiac troponin T values (eg, >7 ng/L over 2 hours) may indicate reinfarction.183 185 During pregnancy, troponin values are within the normal range in the absence of cardiovascular morbidities. There is controversy as to whether troponin levels are elevated in pre- eclampsia, eclampsia, or gestational hypertension.186 189 When present, cardiac troponin elevations reflect myocardial necrosis. Point-of-care troponin values may provide initial diagnostic information, although their sensitivity is substantially below that of central laboratory methods.154,155,190 192 In addition, the rigorous quantitative assay standardization needed for routine diagnosis favors central laboratory testing. Troponin elevations convey prognostic assessment beyond that of clinical information, the initial ECG, and the predischarge In addition, troponin elevations may provide infor- mationtodirecttherapy.Patientswithcardiactroponinelevations Table 5. Summary of Recommendations for Cardiac Biomarkers and the Universal Definition of MI Recommendations COR LOE References Diagnosis Measure cardiac-specific troponin (troponin I or T) at presentation and 3 6 h after symptom onset in all patients with suspected ACS to identify pattern of values Obtain additional troponin levels beyond 6 h in patients with initial normal serial troponins with electrocardiographic changes and/or intermediate/high risk clinical features Consider time of presentation the time of onset with ambiguous symptom onset for assessing troponin values With contemporary troponin assays, CK-MB and myoglobin are not useful for diagnosis of ACS III: No Benefit A 158 164 Prognosis Troponin elevations are useful for short- and long-term prognosis I B 71, 73, 165, 166 Remeasurement of troponin value once on d 3 or 4 in patients with MI may be reasonable as an index of infarct size and dynamics of necrosis BNP may be reasonable for additional prognostic information IIb B 87, 88, 167 171 ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; CK-MB, creatine kinase myocardial isoenzyme; COR, Class of Recommendation; LOE, Level of Evidence; and MI, myocardial infarction. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e359 are at high risk and benefit from intensive management and early High risk is optimally defined by the changing pattern as described in Section 3.4.3. Cardiac troponin elevations correlate with estimation of infarct size and risk of death; persistent elevation 72 to 96 hours after symptom onset may afford relevant information in this regard.164 Elevations of cardiac troponin can occur for multiple reasons other than MI. In these cases, there is often substantial risk of adverse outcomes, as troponin elevation indicates cardiomyocyte necrosis.181 3.4.4. CK-MB and Myoglobin Compared With Troponin Previously, CK-MB was used for early evidence of myocar- dial injury. Because myoglobin is a relatively small molecule, it is rapidly released from infarcted myocardium. CK-MB is much less sensitive for detection of myocardial injury than tro- ponin, and substantially more tissue injury is required for its detection. With the availability of cardiac troponin, CK-MB, myoglobin, and other diagnostic biomarkers are no longer CK-MB may be used to estimate MI size. Detection of MI after percutaneous coronary interven- tion (PCI) remains an area of controversy. Because of the increased sensitivity of cardiac troponin, the prognostic value associated with varying degrees of elevation remains unclear. See Online Data Supplements 5, 6, and 7 for additional information on cardiac injury markers. 3.5. Immediate Management 3.5.1. Discharge From the ED or Chest Pain Unit: Recommendations Class IIa 1. It is reasonable to observe patients with symptoms consistent with ACS without objective evidence of myocardial ischemia (nonischemic initial ECG and normal cardiac troponin) in a chest pain unit or te- lemetry unit with serial ECGs and cardiac troponin at (Level of Evidence: B) 2. It is reasonable for patients with possible ACS who have normal serial ECGs and cardiac troponins to have a treadmill ECG200 202 (Level of Evidence: A), stress myocardial perfusion imaging,200 or stress before discharge or within 72 hours after discharge. (Level of Evidence: B) 3. In patients with possible ACS and a normal ECG, normal cardiac troponins, and no history of CAD, it is reasonable to initially perform (without serial ECGs and troponins) coronary CT angiography to assess coronary artery anatomy205 207 (Level of Evidence: A) or rest myocardial perfusion imaging with a techne- tium-99m radiopharmaceutical to exclude myocar- (Level of Evidence: B) 4. It is reasonable to give low-risk patients who are referred for outpatient testing daily aspirin, short- acting nitroglycerin, and other medication if ap- propriate (eg, beta blockers), with instructions about activity level and clinician follow-up. (Level of Evidence: C) The majority of patients presenting to the ED with chest pain do not have ACS (Figure 1), and most are at low risk for major morbidity and mortality.35 Low-risk patients are usually identi- fied by an absence of history of cardiovascular disease, normal or near-normal initial ECG, normal initial troponin, and clinical The utility of an accelerated diagnostic protocol for detecting patients with benign conditions versus those who require admission for serious disease has been established.35 At minimum, these protocols involve serial ECGs and troponin measurements, both of which can be performed in the ED, a separate chest pain unit, or a telemetry unit. A 30-day negative predictive value >99% for ACS has been reported for patients presenting to the ED with chest pain who undergo a 2-hour accel- erated diagnostic protocol composed of a TIMI risk score of 0, normal ECG, and normal high-sensitivity troponin at 0 hours and 2 hours (assuming appropriate follow-up care).65,210 Some pro- tocols also call for a functional or anatomic test (eg, treadmill test, rest scintigraphy, coronary CT angiography, stress imaging). Coronary CT angiography is associated with rapid assessment, high negative predictive value, decreased length of stay, and ; however, in the latter studies, it increased the rate of invasive coronary angiography and revascularization with uncertain long-term benefits in low-risk patients without ECG or Accelerated diagnostic protocols are also potentially applicable in intermediate-risk patients, whose pre- sentation includes a history of cardiovascular disease, diabetes mellitus, chronic kidney disease (CKD), and/or advanced age.202 See Online Data Supplement 8 for additional information on discharge from the ED or chest pain unit. 4. Early Hospital Care The standard of care for patients who present with NSTE-ACS, including those with recurrent symptoms, ischemic electrocardio- graphic changes, or positive cardiac troponins, is admission for inpatient management. The goals of treatment are the immediate relief of ischemia and the prevention of MI and death. Initially, stabilized patients with NSTE-ACS are admitted to an interme- diate (or step-down) care unit. Patients undergo continuous elec- trocardiographic rhythm monitoring and observation for recurrent ischemia. Bed or chair rest is recommended for patients admit- ted with NSTE-ACS. Patients with NSTE-ACS should be treated with antianginal (Section 4.1.2.5), antiplatelet, and anticoagulant therapy (Section 4.3). Patients are managed with either an early invasive strategy or an ischemia-guided strategy (Section 4.4). Patients with continuing angina, hemodynamic instability, uncontrolled arrhythmias, or a large MI should be admitted to a coronary care unit. The nurse-to-patient ratio should be sufficient to provide 1) continuous electrocardiographic rhythm monitoring, 2) frequent assessment of vital signs and mental status, and 3) abil- ity to perform rapid cardioversion and defibrillation.These patients are usually observed in the coronary care unit for at least 24 hours. Those without recurrent ischemia, significant arrhythmias, pul- monary edema, or hemodynamic instability can be considered for admission or transfer to an intermediate care or telemetry unit. An assessment of LV function is recommended because depressed LV function will likely influence pharmacological therapies (eg, angiotensin-converting enzyme [ACE] inhibitors for depressed left ventricular ejection fraction [LVEF]), may sug- gest the presence of more extensive CAD, and may influence the choice of revascularization (PCI versus coronary artery bypass graft surgery [CABG]). Because significant valvular disease may also influence the type of revascularization, echocardiography rather than ventriculography is often preferred for assessment of LV function. 4.1. Standard Medical Therapies. See Table 6 for a summary of recommendations from this section. 4.1.1. Oxygen: Recommendation Class I 1. Supplemental oxygen should be administered to pa- tients with NSTE-ACS with arterial oxygen satura- tion less than 90%, respiratory distress, or other high- risk features of hypoxemia. (Level of Evidence: C) Patients with cyanosis, arterial oxygen saturation <90%, respira- tory distress, or other high-risk features of hypoxemia are treated with supplemental oxygen. The 2007 UA/NSTEMI CPG recom- mended the routine administration of supplemental oxygen to all patients with NSTE-ACS during the first 6 hours after presenta- tion on the premise that it is safe and may alleviate hypoxemia.212 The benefit of routine supplemental oxygen administration in normoxicpatientswithNSTE-ACShasneverbeendemonstrated. At the time of GWC deliberations, data emerged that routine use of supplemental oxygen in cardiac patients may have untoward effects, including increased coronary vascular resistance, reduced coronary blood flow, and increased risk of mortality.213 215 4.1.2. Anti-Ischemic and Analgesic Medications 4.1.2.1. Nitrates: Recommendations Class I 1. Patients with NSTE-ACS with continuing ischemic pain should receive sublingual nitroglycerin (0.3 mg Table 6. Summary of Recommendations for Early Hospital Care Recommendations COR LOE References Oxygen Administer supplemental oxygen only with oxygen saturation <90%, respiratory distress, or other high-risk features for hypoxemia I C N/A Nitrates Administer sublingual NTG every 5 min 3 for continuing ischemic pain and then assess need for IV NTG I C 216 218 Administer IV NTG for persistent ischemia, HF, or hypertension I B 219 224 Nitrates are contraindicated with recent use of a phosphodiesterase inhibitor III: Harm B 225 227 Analgesic therapy IV morphine sulfate may be reasonable for continued ischemic chest pain despite maximally tolerated anti-ischemic medications NSAIDs (except aspirin) should not be initiated and should be discontinued during hospitalization for NSTE-ACS because of the increased risk of MACE associated with their use III: Harm B 35, 234 Beta-adrenergic blockers Initiate oral beta blockers within the first 24 h in the absence of HF, low-output state, risk for cardiogenic shock, or other contraindications to beta blockade I A 240 242 Use of sustained-release metoprolol succinate, carvedilol, or bisoprolol is recommended for beta-blocker therapy with concomitant NSTE-ACS, stabilized HF, and reduced systolic function I C N/A Re-evaluate to determine subsequent eligibility in patients with initial contraindications to beta blockers I C N/A It is reasonable to continue beta-blocker therapy in patients with normal LV function with NSTE-ACS IIa C 241, 243 IV beta blockers are potentially harmful when risk factors for shock are present III: Harm B 244 CCBs Administer initial therapy with nondihydropyridine CCBs with recurrent ischemia and contraindications to beta blockers in the absence of LV dysfunction, increased risk for cardiogenic shock, PR interval >0.24 s, or second- or third-degree atrioventricular block without a cardiac pacemaker I B 248 250 Administer oral nondihydropyridine calcium antagonists with recurrent ischemia after use of beta blocker and nitrates in the absence of contraindications I C N/A CCBs are recommended for ischemic symptoms when beta blockers are not successful, are contraindicated, or cause unacceptable side effects* I C N/A Long-acting CCBs and nitrates are recommended for patients with coronary artery spasm I C N/A Immediate-release nifedipine is contraindicated in the absence of a beta blocker III: Harm B 251, 252 Cholesterol management Initiate or continue high-intensity statin therapy in patients with no contraindications I A 269 273 Obtain a fasting lipid profile, preferably within 24 h IIa C N/A *Short-acting dihydropyridine calcium channel antagonists should be avoided. CCB indicates calcium channel blocker; COR, Class of Recommendation; HF, heart failure; IV, intravenous; LOE, Level of Evidence; LV, left ventricular; MACE, major adverse cardiac event; N/A, not available; NSAIDs, nonsteroidal anti-inflammatory drugs; NSTE-ACS, non ST-elevation acute coronary syndromes; and NTG, nitroglycerin. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e361 to 0.4 mg) every 5 minutes for up to 3 doses, after which an assessment should be made about the need for intravenous nitroglycerin if not contraindicat- (Level of Evidence: C) 2. Intravenous nitroglycerin is indicated for patients with NSTE-ACS for the treatment of persis- tent ischemia, HF, or hypertension.219 224 (Level of Evidence: B) Class III: Harm 1. Nitrates should not be administered to patients with NSTE-ACS who recently received a phosphodiester- ase inhibitor, especially within 24 hours of sildenafil or vardenafil, or within 48 hours of tadalafil.225 227 (Level of Evidence: B) Nitrates are endothelium-independent vasodilators with peripheral and coronary vascular effects. By dilating the capac- itance vessels, nitrates decrease cardiac preload and reduce ventricular wall tension. More modest effects on the arterial circulation result in afterload reduction and further decrease in . This may be partially offset by reflex increases in heart rate and contractility, which counteract the reduction in MVO2 unless a beta blocker is concurrently administered. Nitrates also dilate normal and atherosclerotic coronary arteries and increase coronary collateral flow. Nitrates may also inhibit RCTs have not shown a reduction in MACE with nitrates. The rationale for nitrate use in NSTE-ACS is extrapolated from pathophysiological principles and extensive (although uncontrolled) clinical observations, experimental studies, and clinical experience. The decision to administer nitrates should not preclude therapy with other proven mortality-reducing interventions such as beta blockers. Intravenous nitroglycerin is beneficial in patients with HF, hypertension, or symptoms that are not relieved with sublin- gual nitroglycerin and administration of a beta blocker.219,221 224 Patients who require intravenous nitroglycerin for >24 hours may require periodic increases in the infusion rate and use of nontolerance-producing regimens (eg, intermittent dosing) to maintain efficacy. In current practice, most patients who require continued intravenous nitroglycerin for the relief of angina undergo prompt coronary angiography and revascular- ization. Topical or oral nitrates are acceptable alternatives to intravenous nitroglycerin for patients who do not have refrac- tory or recurrent ischemia.229,230 Side effects of nitrates include headache and hypotension. Nitrates should not be adminis- tered to patients with hypotension or to those who received a phosphodiesterase inhibitor and are administered with caution to patients with right ventricular infarction.231 See Online Data Supplement 9 for additional information on nitrates. 4.1.2.2. Analgesic Therapy: Recommendations Class IIb 1. In the absence of contraindications, it may be reason- able to administer morphine sulfate intravenously to patients with NSTE-ACS if there is continued ischemic chest pain despite treatment with maximally tolerated (Level of Evidence: B) Class III: Harm 1. Nonsteroidal anti-inflammatory drugs (NSAIDs) (ex- cept aspirin) should not be initiated and should be discontinued during hospitalization for NSTE-ACS because of the increased risk of MACE associated with their use.234,235 (Level of Evidence: B) The role of morphine sulfate was re-evaluated for this CPG revision, including studies that suggest the potential for adverse events with its use.232 Morphine sulfate has potent analgesic and anxiolytic effects, as well as hemodynamic actions, that are potentially beneficial in NSTE-ACS. It causes venodilation and produces modest reductions in heart rate (through increased vagal tone) and systolic BP. In patients with symptoms despite antianginal treatment, morphine (1 mg to 5 mg IV) may be administered during intravenous nitroglycerin therapy with BP monitoring. The morphine dose may be repeated every 5 to 30 minutes to relieve symptoms and maintain the patient s comfort. Its use should not preclude the use of other anti-ischemic therapies with proven benefits in patients with NSTE-ACS. To our knowledge, no RCTs have assessed the use of morphine in patients with NSTE-ACS or defined its optimal administration schedule. Observational studies have demonstrated increased adverse events associ- ated with the use of morphine sulfate in patients with ACS and acute decompensated HF.232,233,236 Although these reports were observational, uncontrolled studies limited by selection bias, they raised important safety concerns. Although constipation, nausea, and/or vomiting occur in >20% of patients, hypotension and respiratory depression are the most serious complications of excessive use of mor- phine. Naloxone (0.4 mg to 2.0 mg IV) may be adminis- tered for morphine overdose with respiratory or circulatory depression. Traditional NSAIDs and selective cyclooxygenase (COX)-2 inhibitors markedly block endothelial prostacyclin production, which leads to unopposed platelet aggregation by platelet-derived thromboxane A2 . Both types of NSAIDs prevent the beneficial actions of aspirin and interfere with the inhibition of COX-1, thromboxane A2 production, and platelet aggregation. Because of their inhibitory activity on the ubiq- uitous COXs, NSAIDs have an extensive adverse side effect profile, particularly renal and gastrointestinal. The increased cardiovascular hazards associated with NSAIDs have been observed in several studies of patients without ACS.234,235,237,238 The PRECISION (Prospective Randomized Evaluation of Celecoxib Integrated Safety Versus Ibuprofen Or Naproxen) trial, in progress at the time of publication, is the first study of patients with high cardiovascular risk who are receiving long- term treatment with a selective COX-2 inhibitor or traditional NSAIDs. PRECISION will examine the relative cardiovas- cular safety profiles of celecoxib, ibuprofen, and naproxen in patients without ACS.239 See Online Data Supplement 10 for additional information on analgesic therapy. 4.1.2.3. Beta-Adrenergic Blockers: Recommendations Class I 1. Oral beta-blocker therapy should be initiated with- in the first 24 hours in patients who do not have any of the following: 1) signs of HF, 2) evidence of low-output state, 3) increased risk for cardiogenic shock, or 4) other contraindications to beta block- ade (eg, PR interval >0.24 second, second- or third- degree heart block without a cardiac pacemaker, active asthma, or reactive airway disease).240 242 (Level of Evidence: A) 2. In patients with concomitant NSTE-ACS, stabilized HF, and reduced systolic function, it is recommended to continue beta-blocker therapy with 1 of the 3 drugs proven to reduce mortality in patients with HF: sus- tained-release metoprolol succinate, carvedilol, or bi- soprolol. (Level of Evidence: C) 3. Patients with documented contraindications to beta blockers in the first 24 hours of NSTE-ACS should be re-evaluated to determine their subsequent eligibility. (Level of Evidence: C) Class IIa 1. It is reasonable to continue beta-blocker therapy in patients with normal LV function with NSTE- (Level of Evidence: C) Class III: Harm 1. Administration of intravenous beta blockers is poten- tially harmful in patients with NSTE-ACS who have risk factors for shock.244 (Level of Evidence: B) Beta blockers decrease heart rate, contractility, and BP, result- ing in decreased MVO2 . Beta blockers without increased sympathomimetic activity should be administered orally in the absence of contraindications. Although early administra- tion does not reduce short-term mortality,241,244 beta blockers decrease myocardial ischemia, reinfarction, and the frequency of complex ventricular dysrhythmias,240,245 and they increase long-term survival. Early beta blockade, particularly if given intravenously, can increase the likelihood of shock in patients with risk factors. Risk factors for shock include patients >70 years of age, heart rate >110 beats per minute, systolic BP <120 mmHg, and late presentation.244 In patients with LV dys- function (LVEF <0.40) with or without pulmonary congestion, beta blockers are strongly recommended before discharge. Beta blockers should be used prudently with ACE inhibitors or angiotensin-receptor blockers (ARBs) in patients with HF. Renin-angiotensin-aldosterone system blocking agents should be cautiously added in patients with decompensated HF.246 Beta blockers without intrinsic sympathomimetic activity should be used, especially beta-1 blockers such as sustained- release metoprolol succinate, bisoprolol, or carvedilol, a beta-1 and alpha-1 blocker. This is because of their mortality benefit in patients with HF and systolic dysfunction.246,247 In patients with chronic obstructive lung disease or a history of asthma, beta blockers are not contraindicated in the absence of active bronchospasm. Beta-1 selective beta blockers are preferred and should be initiated at a low dosage. See Online Data Supplement 11 for additional information on beta blockers, including risk factors for shock. 4.1.2.4. Calcium Channel Blockers: Recommendations Class I 1. In patients with NSTE-ACS, continuing or frequent- ly recurring ischemia, and a contraindication to beta blockers, a nondihydropyridine calcium channel blocker (CCB) (eg, verapamil or diltiazem) should be given as initial therapy in the absence of clinically significant LV dysfunction, increased risk for cardio- genic shock, PR interval greater than 0.24 second, or second- or third-degree atrioventricular block with- out a cardiac pacemaker.248 250 (Level of Evidence: B) 2. Oral nondihydropyridine calcium antagonists are recommended in patients with NSTE-ACS who have recurrent ischemia in the absence of contra- indications, after appropriate use of beta blockers and nitrates. (Level of Evidence: C) 3. CCBs are recommended for ischemic symptoms when beta blockers are not successful, are contrain- dicated, or cause unacceptable side effects. (Level of Evidence: C) 4. Long-acting CCBs and nitrates are recommended in patients with coronary artery spasm. (Level of Evi- dence: C) Class III: Harm 1. Immediate-release nifedipine should not be adminis- tered to patients with NSTE-ACS in the absence of (Level of Evidence: B) CCBs include dihydropyridines and nondihydropyridines. The dihydropyridines (nifedipine and amlodipine) produce the most marked peripheral vasodilation and have little direct effect on contractility, atrioventricular conduction, and heart rate. The nondihydropyridines (diltiazem and verapamil) have significant negative inotropic actions and negative chronotropic and drom- otropic effects. All CCBs cause similar coronary vasodilation and are preferred in vasospastic angina.253 They also alleviate ischemia due to obstructive CAD by decreasing heart rate and BP. Verapamil and diltiazem decreased reinfarction in patients without LV dysfunction in some248,249,254 but not all studies.255,256 Verapamil may be beneficial in reducing long-term events after AMI in hypertensive patients without LV dysfunction250 and in patients with MI and HF receiving an ACE inhibitor.257 Immediate-release nifedipine causes a dose-related increase in mortality in patients with CAD and harm in ACS and is not recommended for routine use in patients with ACS.251,258 Long- acting preparations may be useful in older patients with systolic There are no significant trial data on efficacy of amlodipine or felodipine in patients with NSTE-ACS. See Online Data Supplement 12 for additional information on CCBs. Short-acting dihydropyridine calcium channel antagonists should be avoided. Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e363 4.1.2.5. Other Anti-Ischemic Interventions Ranolazine Ranolazine is an antianginal medication with minimal effects on heart rate and BP.260,261 It inhibits the late inward sodium cur- rent and reduces the deleterious effects of intracellular sodium and calcium overload that accompany myocardial ischemia.262 Ranolazine is currently indicated for treatment of chronic angina. The MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non ST-Elevation Acute Coronary Syndromes-Thrombosis In Myocardial Infarction) 36 trial examined the efficacy and safety of ranolazine in 6560 patients with NSTE-ACS who presented within 48 hours of In a post hoc analysis in women, rano- lazine was associated with a reduced incidence of the primary endpoint (cardiovascular death, MI, or recurrent ischemia), principally owing to a 29% reduction in recurrent ischemia.116 In the subgroup with prior chronic angina (n=3565), ranola- zine was associated with a lower primary composite endpoint, a significant reduction of worsening angina, and increased Because the primary endpoint of the original MERLIN-TIMI 36 trial was not met, all additional analyses should be interpreted with caution. The recom- mended initial dose is 500 mg orally twice daily, which can be uptitrated to a maximum of 1000 mg orally twice daily. Ranolazine is usually well tolerated; its major adverse effects are constipation, nausea, dizziness, and headache. Ranolazine prolongs the QTc interval in a dose-related manner, but QTc prolongation requiring dose reduction was comparable with ranolazine and placebo in the MERLIN-TIMI 36 trial.263 See Online Data Supplement 13 for additional information on ranolazine. Intra-Aortic Balloon Pump (IABP) Counterpulsation IABP counterpulsation may be used in patients with NSTE- ACS to treat severe persistent or recurrent ischemia, especially in patients awaiting invasive angiography and revascular- ization, despite intensive medical therapy. In experimental studies, IABP counterpulsation increases diastolic BP and coronary blood flow and potentially augments cardiac output while diminishing LV end-diastolic pressure. The use of IABP for refractory ischemia dates back several decades, and its current application is predominantly driven by clinical experi- ence and nonrandomized observational studies.265 When stud- ied in rigorous RCTs, IABP counterpulsation failed to reduce MACE in high-risk elective PCI,266 decrease infarct size after primary PCI for acute STEMI,267 or diminish early mortality in patients with cardiogenic shock complicating AMI.268 4.1.2.6. Cholesterol Management Class I 1. High-intensity statin therapy should be initiated or continued in all patients with NSTE-ACS and no con- traindications to its use.269 273 (Level of Evidence: A) Class IIa 1. It is reasonable to obtain a fasting lipid profile in pa- tients with NSTE-ACS, preferably within 24 hours of presentation. (Level of Evidence: C) Therapy with statins in patients with NSTE-ACS reduces the rate of recurrent MI, coronary heart disease mortality, need for myocardial revascularization, and stroke. High-risk patients, such as those with NSTE-ACS, derive more benefit in reducing these events from high-intensity statins, such as atorvastatin which lower low-density lipoprotein cholesterol levels by 50% as in the PROVE IT-TIMI 22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) and MIRACL (Myocardial Ischemia Reduction With Acute Cholesterol Lowering) trials,273,274 than from moderate- or low-intensity statins.18,272 These findings provide the basis for high-intensity statin therapy after stabi- lization of patients with NSTE-ACS. In addition, early intro- duction of this approach can promote improved compliance with this regimen. 4.2. Inhibitors of the Renin-Angiotensin- Aldosterone System: Recommendations Class I 1. ACE inhibitors should be started and continued in- definitely in all patients with LVEF less than 0.40 and in those with hypertension, diabetes mellitus, or sta- ble CKD (Section 7.6), unless contraindicated.275,276 (Level of Evidence: A) 2. ARBs are recommended in patients with HF or MI with LVEF less than 0.40 who are ACE inhibitor in- (Level of Evidence: A) 3. Aldosterone blockade is recommended in patients post MI without significant renal dysfunction (cre- atinine >2.5 mg/dL in men or >2.0 mg/dL in women) or hyperkalemia (K+ >5.0 mEq/L) who are receiving therapeutic doses of ACE inhibitor and beta blocker and have a LVEF 0.40 or less, diabetes mellitus, or (Level of Evidence: A) Class IIa 1. ARBs are reasonable in other patients with cardiac or other vascular disease who are ACE inhibitor in- (Level of Evidence: B) Class IIb 1. ACE inhibitors may be reasonable in all other pa- tients with cardiac or other vascular disease.281,282 (Level of Evidence: B) ACE inhibitors reduce mortality in patients with recent MI, primarily those with LV dysfunction (LVEF <0.40) with or without pulmonary congestion.283 285 In patients with normal LV function (including patients with diabetes mellitus), total mortality and MACE (including HF) are reduced. It has been found that approximately 15% of patients with NSTEMI develop HF during hospitalization, with the rate increas- ing to 24% of patients 1 year later.286 A metaanalysis dem- onstrated a small but significant (0.48%) absolute benefit of early initiation of an ACE inhibitor on survival at 30 days, with benefit seen as early as 24 hours after admission for An ACE inhibitor should be used cautiously in the first 24 hours of AMI, because it may result in hypotension or renal dysfunction.283 It may be prudent to initially use a short-acting ACE inhibitor, such as captopril or enalapril, in patients at increased risk of these adverse events. In patients with significant renal dysfunction, it is sensible to stabilize renal function before initiating an ACE inhibitor or an ARB, with re-evaluation of creatinine levels after drug initiation. An ARB may be substituted for an ACE inhibitor with similar benefits on survival.277,278 Combining an ACE inhibitor and an ARB may result in an increase in adverse events.277,278 In a study in which patients with AMI with LV dysfunction (LVEF <0.40) with or without HF were randomized 3 to 14 days after AMI to receive eplerenone (a selective aldosterone blocker), eplerenone was efficacious as an adjunct to ACE inhibitors and beta blockers in decreasing long-term mortality.279,287 In a study of patients with HF, >50% of whom had an ischemic etiology, spironolactone (a nonselective aldosterone inhibitor) ; however, RCT data on MI are not available. See Online Data Supplement 14 for additional information on inhibitors of the renin-angiotensin-aldosterone system. 4.3. Initial Antiplatelet/Anticoagulant Therapy in Patients With Definite or Likely NSTE-ACS 4.3.1. Initial Oral and Intravenous Antiplatelet Therapy in Patients With Definite or Likely NSTE-ACS Treated With an Initial Invasive or Ischemia-Guided Strategy: Recommendations See Table 7 for a summary of recommendations from this section and Online Data Supplement 15 for additional infor- mation on initial oral and intravenous antiplatelet therapy in patients with definite or likely NSTE-ACS treated with an early invasive or an ischemia-guided strategy. Class I 1. Non enteric-coated, chewable aspirin (162 mg to 325 mg) I should be given to all patients with NSTE- ACS without contraindications as soon as possible after presentation, and a maintenance dose of aspirin (81 mg/d to 325 mg/d) should be continued indefinite- (Level of Evidence: A) 2. In patients with NSTE-ACS who are unable to take aspirin because of hypersensitivity or major gastro- intestinal intolerance, a loading dose of clopidogrel followed by a daily maintenance dose should be ad- (Level of Evidence: B) inhibitor (either clopidogrel or ticagrelor) in addition to aspirin should be administered for up to 12 months to all patients with NSTE-ACS without con- traindications who are treated with either an early in- vasive or ischemia-guided strategy. Options include: Clopidogrel: 300-mg or 600-mg loading dose, then (Level of Evidence: B) Ticagrelor : 180-mg loading dose, then 90 mg (Level of Evidence: B) Class IIa 1. It is reasonable to use ticagrelor in preference to clop- idogrel for P2Y12 treatment in patients with NSTE- ACS who undergo an early invasive or ischemia- (Level of Evidence: B) Class IIb 1. In patients with NSTE-ACS treated with an early inva- sive strategy and dual antiplatelet therapy (DAPT) with intermediate/high-risk features (eg, positive troponin), a GP IIb/IIIa inhibitor may be considered as part of ini- tial antiplatelet therapy. Preferred options are eptifiba- tide or tirofiban.43,94,295 (Level of Evidence: B) Despite the large number of new antiplatelet and antithrombotic agents, aspirin, which targets COX and subsequent throm- inhibition, is the mainstay of antiplatelet therapy. Multiple other pathways of platelet activation can be targeted by agents that inhibit the platelet P2Y12 receptor, including thi- enopyridine prodrug agents, such as clopidogrel and prasugrel, which require conversion into molecules that bind irreversibly to the P2Y12 receptor.Additional pyrimidine derivatives, includ- ing ticagrelor, do not require biotransformation and bind revers- ibly to the P2Y12 receptor, antagonizing adenosine diphosphate platelet activation. In addition to these oral agents, intravenous GP IIb/IIIa receptor inhibitors, including abciximab, eptifiba- tide, and tirofiban, target the final common pathway of platelet aggregation. In the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non ST-Segment Elevation Acute Coronary Syndrome) trial, patients were randomly assigned to either early, pre PCI double-bolus eptifibatide or delayed, provisional eptifibatide. Seventy-five percent of the patients received upstream, preprocedure clopidogrel. The risk of TIMI major bleeding in the early eptifibatide group was 2.6% com- pared with 1.8% (P=0.02) in the delayed provisional group.295 In the GUSTO IV-ACS (Global Use of Strategies To Open Occluded Coronary Arteries IV-Acute Coronary Syndromes) trial, there was no clinical benefit of abciximab in this popu- lation; in troponin-negative patients, mortality was 8.5% com- pared with 5.8% in controls (P=0.002).288,289,296,297 Aspirin is the established first-line therapy in patients with NSTE-ACS and reduces the incidence of recurrent MI and A loading dose of non enteric-coated aspirin 162 mg to 325 mg is the initial antiplatelet therapy. The subse- quent maintenance dose is 81 mg per day to 162 mg per day; in special circumstances, a higher maintenance dose up to 325 mg daily has been used.391 The lower dose is favored and all patients treated with ticagrelor should receive only 81 mg In other countries, available low-dose aspirin for- mations may include 75 mg and 100 mg. High-dose ( 160 mg) versus low-dose (<l60 mg) aspirin is associated with increased bleeding risk in the absence of improved outcomes.298 Most NSAIDs reversibly bind to COX-1, preventing inhibition by aspirin and by COX-2 and may cause prothrombotic effects. Enteric-coated aspirin should be avoided initially because of its delayed and reduced absorption.299 See Section 5.1.2.1 for recommendations at the time of PCI. See Section 4.3.1.2 for prasugrel indications in either an early invasive or ischemia-guided strategy. The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.290 Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e365 Receptor Inhibitors receptor inhibitors are approved in the United States for treatment of ischemic myocardial disorders, including NSTE-ACS. For discontinuation before surgery, see Section 5. Clopidogrel Administration of clopidogrel with aspirin was superior to administration of aspirin alone in reducing the incidence of cardiovascular death and nonfatal MI or stroke both acutely and over the following 11 months.289,296 There was a slight increase in major bleeding events with clopidogrel, including a nonsignificant increase in life-threatening bleeding and fatal An initial loading dose of 300 mg to 600 mg is rec- A 600-mg loading dose results in a greater, more rapid, and more reliable platelet inhibition compared with a 300-mg loading dose.301 Use of clopidogrel for patients with NSTE-ACS who are aspirin intolerant is based on a study Table 7. Summary of Recommendations for Initial Antiplatelet/Anticoagulant Therapy in Patients With Definite or Likely NSTE-ACS and PCI Recommendations Dosing and Special Considerations COR LOE References Aspirin Non enteric-coated aspirin to all patients promptly after presentation Aspirin maintenance dose continued indefinitely 81 mg/d-325 mg/d* I A 288 290, inhibitors Clopidogrel loading dose followed by daily maintenance dose in patients unable to take aspirin 75 mg I B 291 inhibitor, in addition to aspirin, for up to 12 mo for patients treated initially with either an early invasive or initial ischemia- guided strategy: Clopidogrel Ticagrelor* 300-mg or 600-mg loading dose, then 75 mg/d I B 180-mg loading dose, then 90 mg BID inhibitor therapy (clopidogrel, prasugrel, or ticagrelor) continued for at least 12 mo in post PCI patients treated with coronary stents N/A I B Ticagrelor in preference to clopidogrel for patients treated with an early invasive or ischemia-guided strategy N/A IIa B 293, 294 GP IIb/IIIa inhibitors GP IIb/IIIa inhibitor in patients treated with an early invasive strategy and DAPT with intermediate/high-risk features (eg, positive troponin) Preferred options are eptifibatide Parenteral anticoagulant and fibrinolytic therapy SC enoxaparin for duration of hospitalization or until PCI is performed 1 mg/kg SC every 12 h (reduce dose to 1 mg/kg/d SC in patients with CrCl Initial 30 mg IV loading dose in selected patients Bivalirudin until diagnostic angiography or PCI is performed in patients with early invasive strategy only Loading dose 0.10 mg/kg loading dose followed by 0.25 mg/kg/h Only provisional use of GP IIb/IIIa inhibitor in patients also treated with DAPT I B SC fondaparinux for the duration of hospitalization or until PCI is performed 2.5 mg SC daily I B 312 314 Administer additional anticoagulant with anti-IIa activity if PCI is performed while patient is on fondaparinux N/A I B 313 315 IV UFH for 48 h or until PCI is performed Initial loading dose 60 IU/kg (max 4000 IU) with initial infusion 12 IU/kg/h (max 1000 IU/ h) Adjusted to therapeutic aPTT range I B 316 322 IV fibrinolytic treatment not recommended in patients with NSTE-ACS N/A III: Harm A 93, 329 See Section 5.1.2.1 for recommendations on antiplatelet/anticoagulant therapy at the time of PCI and Sections 6.2.1 and 6.3 for recommendations on posthospital therapy. *The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily.290 aPTT indicates activated partial thromboplastin time; BID, twice daily; COR, Class of Recommendation; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; GP, glycoprotein; IV, intravenous; LOE, Level of Evidence; max, maximum; N/A, not available; NSTE-ACS, non-ST-elevation acute coronary syndromes; PCI, percutaneous coronary intervention; SC, subcutaneous; and UFH, unfractionated heparin. in patients with stable ischemic heart disease.291 When pos- sible, discontinue clopidogrel at least 5 days before surgery.301 Prasugrel The metabolic conversion pathways of prasugrel produce more rapid and consistent platelet inhibition than clopido- In patients with NSTE-ACS and defined coronary anatomy undergoing planned PCI, a 60-mg loading dose of prasugrel followed by 10 mg daily was compared with a 300-mg loading dose and 75 mg daily of clopidogrel. The composite primary endpoint (cardiovascular death, nonfatal MI, and stroke) was reduced in patients treated with prasu- grel (hazard ratio [HR]: 0.81; P=0.001). This was driven by a risk reduction for MI and stent thrombosis with no differ- ence in mortality.302 Counterbalancing the salutary effects of prasugrel was a significant increase in spontaneous bleeding, life-threatening bleeding, and fatal bleeding in the patients treated with prasugrel compared with patients treated with clopidogrel. There was net harm in patients with a history of cerebrovascular events and no clinical benefit in patients >75 years of age or those with low body weight (<60 kg).302 In patients with NSTE-ACS treated with an ischemia-guided strategy, 1 RCT comparing aspirin and either clopidogrel or prasugrel evaluated the primary endpoint of death from car- diovascular causes, MI, or stroke for up to 30 months; there were similar bleeding rates and no benefit of treatment with prasugrel when compared with treatment with clopidogrel.303 The ACCOAST (A Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients With Non ST-Elevation Myocardial Infarction) RCT of high-risk patients with NSTE- ACS scheduled to undergo early coronary angiography found that a strategy of administration of prasugrel at the time of randomization before angiography did not lead to a reduc- tion in the composite primary endpoint when compared with a strategy of administration of prasugrel only at the time of PCI; however, it did lead to an increase in bleeding complica- On the basis of TRITON (Trial toAssess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel) study design and the results of TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) and ACCOAST, prasugrel is not recommended for upfront therapy in patients with NSTE-ACS. The use of prasugrel in patients undergoing PCI is addressed in Section 5. Ticagrelor Ticagrelor is an oral, reversibly binding P2Y12 inhibitor with a relatively short plasma half-life (12 hours). Compared with clopidogrel, ticagrelor has a more rapid and consistent onset of action and, because it is reversible, it has a faster recovery of platelet function. The loading dose of ticagrelor for patients treated either invasively or with an ischemia-guided strategy is 180 mg followed by a maintenance dose of 90 mg twice In patients with NSTE-ACS treated with ticagrelor compared with clopidogrel, there was a reduction in the com- posite outcome of death from vascular causes, MI, or stroke The mor- tality rate was also lower in those patients treated with ticagre- lor. Although overall major bleeding was not increased with ticagrelor, a modest increase in major bleeding and non pro- cedure-related bleeding occurred in the subgroup of patients who did not undergo CABG (major bleeding: 4.5% versus 2.3%; P=0.05); however, there was no difference in blood transfusion or fatal bleeding.305 Side effects unique to ticagre- lor include dyspnea (which occurs in up to 15% of patients within the first week of treatment but is rarely severe enough to cause discontinuation of treatment)293 and bradycardia. The benefit of ticagrelor over clopidogrel was limited to patients taking 75 mg to 100 mg of aspirin.290 The short half-life requires twice-daily administration, which could potentially result in adverse events in non-compliant patients, particularly after stent implantation. When possible, ticagrelor should be discontinued at least 5 days before surgery.306 Although ticagrelor has not been studied in the absence of aspirin, its use in aspirin-intolerant patients is a reasonable alternative. Intravenous GP IIb/IIIa Receptor Inhibitors The small molecule GP IIb/IIIa receptor antagonists, tirofiban and eptifibatide, bind reversibly to the GP IIb/IIIa receptor. Because the drug-to-receptor ratio is high, platelet infusion is not effective in cases of severe bleeding after use of eptifiba- tide or tirofiban, and they must be cleared from the circulation to reduce bleeding. In contrast, with abciximab, the drug-to- receptor ratio is low, and platelet infusion may be effective. Several large RCTs evaluated the impact of GP IIb/IIIa receptor inhibitors in patients with NSTE-ACS who were committed to an invasive strategy.295,296,306 TheACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial evaluated unfractionated heparin (UFH) versus bivalirudin with or without GP IIb/IIIa inhibitors.295,307 The rates of composite ischemia (death, MI, unplanned revascularization) in patients who received bivalirudin alone compared with those who received UFH plus GP IIb/IIIa inhibitors were similar (9% ver- Fewer patients experienced major bleeding with bivalirudin alone than did with heparin plus GP IIb/IIIa inhibitors (4% versus 7%; relative risk [RR]: 0.52; 95% confi- The ACUITY Timing trial evaluated the benefit of upstream GP IIb/IIIa receptor antagonist compared with its deferred use, testing the hypothesis that earlier administration of GP IIb/IIIa inhibitors in patients destined for PCI would be superior.308 Composite ischemia at 30 days occurred in 7.9% of patients assigned to deferred use compared with 7.1% assigned to upstream admin- riority; P=0.13 for superiority). Deferred GP IIb/IIIa inhibitors reduced the 30-day rates of major bleeding compared with Similar results were reported by the EARLYACS investigators, who evaluated eptifibatide given upstream versus delayed, provisional admin- istration in >9000 patients with NSTE-ACS.295 The compos- ite endpoint of death, MI, recurrent ischemia requiring urgent revascularization, or thrombotic complications occurred in 9.3% of patients in the early-eptifibatide group compared with 10% in the delayed-eptifibatide group (odds ratio [OR]: 0.92; As in the ACUITY Timing trial, the early-eptifibatide group had significantly higher rates of bleeding and red cell transfusions.295,308 Amsterdam et al 2014 AHA/ACC NSTE-ACS Guideline e367 4.3.2. Initial Parenteral Anticoagulant Therapy in Patients With Definite NSTE-ACS: Recommendations See Table 7 for a summary of recommendations regarding antiplatelet/anticoagulant therapy in patients with definite or likely NSTE-ACS and Online Data Supplement 16 for addi- tional information on combined oral anticoagulant therapy and antiplatelet therapy in patients with definite NSTE-ACS. Class I 1. In patients with NSTE-ACS, anticoagulation, in ad- dition to antiplatelet therapy, is recommended for all patients irrespective of initial treatment strategy. Treatment options include: Enoxaparin: 1 mg/kg subcutaneous (SC) every 12 hours (reduce dose to 1 mg/kg SC once daily in patients with creatinine clearance [CrCl] <30 mL/min), continued for the duration of hos- pitalization or until PCI is performed. An initial intravenous loading dose of 30 mg has been used in selected patients.133,136,309 (Level of Evidence: A) Bivalirudin: 0.10 mg/kg loading dose followed by 0.25 mg/kg per hour (only in patients managed with an early invasive strategy), continued until diagnostic angiography or PCI, with only provi- sional use of GP IIb/IIIa inhibitor, provided the patient is also treated with DAPT.292,293,310,311 (Level of Evidence: B) Fondaparinux: 2.5 mg SC daily, continued for the duration of hospitalization or until PCI is per- (Level of Evidence: B) If PCI is performed while the patient is on fondaparinux, an additional anticoagulant with anti-IIa activity (either UFH or bivalirudin) should be administered because of the risk of catheter (Level of Evidence: B) UFH IV: initial loading dose of 60 IU/kg (maxi- mum 4000 IU) with initial infusion of 12 IU/kg per hour (maximum 1000 IU/h) adjusted per activated partial thromboplastin time to maintain therapeu- tic anticoagulation according to the specific hospi- tal protocol, continued for 48 hours or until PCI is (Level of Evidence: B) 4.3.2.1. Low-Molecular-Weight Heparin LMWHs have a molecular weight approximately one third that of UFH and have balanced anti-Xa and anti-IIa activity. LMWHs are readily absorbed after subcutaneous administration and have less platelet activation.323 The anticoagulant activity of LMWH does not require routine monitoring. The dose of enoxaparin is 1 mg/kg SC every 12 hours for NSTE-ACS; an initial intravenous loading dose of 30 mg has been used in selected patients. In the presence of impaired renal function (CrCl <30 mL per minute), which is a common finding in older patients, the dose should be reduced to 1 mg/kg SC once daily, and strong consideration should be given to UFH as an alternative. Calculation of CrCl is prudent in patients considered for enoxaparin therapy. In the ESSENCE trial, in patients with UA or non Q-wave MI, the rates of recurrent ischemic events and invasive diagnostic and therapeutic procedures were significantly reduced by enoxaparin therapy in the short term, and benefit was sustained at 1 year.324 In the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors) trial of high-risk patients with NSTE-ACS treated with an early invasive strategy, there was no significant difference in death or MI at 30 days between those randomized to enoxapa- rin versus UFH. There was more TIMI major bleeding in those treated with enoxaparin without statistically significant increase in GUSTO severe bleeding or transfusion. Some of the increased bleeding may have been related to patients randomized to enoxa- parin who received additional UFH at the time of PCI.325,326 The direct thrombin inhibitor bivalirudin is administered intra- venously. Bivalirudin was evaluated in the ACUITY trial, a randomized open-label trial, in 13819 moderate- to high-risk patients with NSTE-ACS with a planned invasive strategy. Three treatment arms were tested, including UFH or LMWH with a GP IIb/IIIa receptor inhibitor, bivalirudin with a GP IIb/IIIa receptor inhibitor, or bivalirudin alone. The majority of patients received clopidogrel (300 mg) before interven- tion, in addition to aspirin, anticoagulants, and GP IIb/IIIa inhibitors. Bivalirudin alone was noninferior to the standard UFH/LMWH combined with GP IIb/IIIa inhibitor (composite there was a significantly lower rate of major bleeding with The anticoagulant effect of bivalirudin can be monitored in the catheterization laboratory by the activated clotting time. Fondaparinux is a synthetic polysaccharide molecule and the only selective inhibitor of activated factor X available for clinical use. Fondaparinux is well absorbed when given sub- cutaneously and has a half-life of 17 hours, enabling once- daily administration. Because it is excreted by the kidneys, it is contraindicated if CrCl is <30 mL per minute. Monitoring of anti-Xa activity is not required, and fondaparinux does not affect usual anticoagulant parameters such as activated partial thromboplastin time or activated clotting time. In NSTE-ACS, the dose of fondaparinux is 2.5 mg SC administered daily and continued for the duration of hospitalization or until PCI is per- In the OASIS (Organization to Assess Strategies in Ischemic Syndromes)-5 study, patients with NSTE-ACS were randomized to receive 2.5 mg SC fondaparinux daily or enoxaparin 1 mg/kg SC twice daily for 8 days. The inci- dence of the primary composite ischemic endpoint at 9 days was similar between fondaparinux and enoxaparin, but major bleeding was significantly less frequent with fondaparinux. To avert catheter thrombosis when fondaparinux is used alone in patients undergoing PCI, an anticoagulant with anti-IIa activ- ity is also administered.313 315 One regimen is 85 IU/kg of UFH loading dose at the time of PCI (reduced to 60 IU/kg if a GP IIb/IIIa inhibitor is used concomitantly).314 4.3.2.4. Unfractionated Heparin Studies supporting the addition of a parenteral anticoagulant to aspirin in patients with NSTE-ACS were performed primar- ily on patients with a diagnosis of unstable angina in the era before DAPT and early catheterization and revascularization. See Section 5.1.2.1 for recommendations at the time of PCI. In general, those studies found a strong trend for reduction in composite adverse events with the addition of parenteral UFH to aspirin therapy.316 322 Clinical trials indicate that a weight-adjusted dosing regi- men of UFH can provide more predictable anticoagulation327 than a fixed initial dose (eg, 5000 IU loading dose, 1000 IU/h initial infusion). The recommended weight-adjusted regimen is an initial loading dose of 60 IU/kg (maximum 4000 IU) and an initial infusion of 12 IU/kg/h (maximum 1000 IU/h), adjusted using a standardized nomogram. Argatroban, a direct thrombin inhibitor, is indicated for pro- phylaxis or treatment of thrombosis in patients with heparin- induced thrombocytopenia, including those undergoing PCI.328 Steady state plasma concentrations are achieved in 1 to 3 hours after intravenous administration. Because of its hepatic metab- olism, argatroban can be used in patients with renal insuffi- ciency. The usual dose is 2 mcg/kg per minute by continuous intravenous infusion, adjusted to maintain the activated partial thromboplastin time at 1.5 to 3 times baseline (but not >100 s). 4.3.3. Fibrinolytic Therapy in Patients With Definite NSTE-ACS: Recommendation Class III: Harm 1. In patients with NSTE-ACS (ie, without ST-elevation, true posterior MI, or left bundle-branch block not known to be old), intravenous fibrinolytic therapy should not be used.93,329 (Level of Evidence: A) There is no role for fibrinolytic therapy in patients with NSTE- ACS. Fibrinolysis with or without subsequent PCI in patients with NSTE-ACS was evaluated by the Fibrinolytic Trialists and There was no benefit for mortality or MI. Intracranial hemorrhage and fatal and nonfatal MI occurred more frequently in patients treated with fibrinolytic therapy. See Online Data Supplement 17 for additional informa- tion on parenteral anticoagulant and fibrinolytic therapy in patients with definite NSTE-ACS. 4.4. Ischemia-Guided Strategy Versus Early Invasive Strategies See Figure 3 for the management algorithm for ischemia- guided versus early invasive strategy. 4.4.1. General Principles Two treatment pathways have emerged for all patients with NSTE-ACS. The invasive strategy triages patients to an inva- sive diagnostic evaluation (ie, coronary angiography). In contrast, the initial ischemia-guided strategy calls for an inva- sive evaluation for those patients who 1) fail medical therapy (refractory angina or angina at rest or with minimal activity despite vigorous medical therapy), 2) have objective evidence of ischemia (dynamic electrocardiographic changes, myo- cardial perfusion defect) as identified on a noninvasive stress test, or 3) have clinical indicators of very high prognostic risk (eg, high TIMI or GRACE scores). In both strategies, patients should receive optimal anti-ischemic and antithrombotic medical therapy as outlined in Section 4.1. A subgroup of patients with refractory ischemic symptoms or hemodynamic or rhythm instability are candidates for urgent coronary angi- ography and revascularization. 4.4.2. Rationale and Timing for Early Invasive Strategy This strategy seeks to rapidly risk stratify patients by assess- ing their coronary anatomy. The major advantages of invasive therapy when appropriate are 1) the rapid and definitive nature of the evaluation, 2) the potential for earlier revascularization in appropriate patients that might prevent occurrence of fur- ther complications of ACS that could ensue during medical therapy, and 3) facilitation of earlier discharge from a facility. 4.4.2.1. Routine Invasive Strategy Timing The optimal timing of angiography has not been conclusively defined. In general, 2 options have emerged: early invasive (ie, within 24 hours) or delayed invasive (ie, within 25 to 72 hours). In most studies using the invasive strategy, angiogra- phy was deferred for 12 to 72 hours while antithrombotic and anti-ischemic therapies were intensified.138,332 337 The concept of deferred angiography espouses that revascularization may be safer once plaque is stabilized with optimal antithrombotic and/or anti-ischemic therapies. Conversely, early angiography facilitates earlier risk stratification and consequently speeds revascularization and discharge but can place greater logistic demands on a healthcare system. 4.4.3. 