WORKUP	Section 5 of 11
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Lab Studies:

• The following laboratory studies are recommended in the evaluation of the patient with unstable angina: (1) serial cardiac markers, (2) hemogloblin, (3) serum chemistry, (4) lipid panel within 24 hours of presentation. A number of cardiac biomarker assays are currently available for the diagnosis of myocardial cell necrosis. Some of these, especially the troponin assays, are powerful prognostic tools as well and serve as important guides to the aggressiveness of approach.

• Cardiac enzymes

• The current standard of care includes drawing blood for total creatine kinase (CK) and its MB isoenzyme (CK-MB) every 6-8 hours during the first 24 hours. Also, determine cardiac-specific troponin (T or I) levels at least twice, 6-8 hours apart, because these may be initially negative, especially within 2-4 hours of chest pain.

• Consider additional measurements of CK-MB, or troponin if initially negative, for patients who have persistent or recurrent symptoms or if index of suspicion is high.

• Absolute elevations of CK-MB or troponin levels are highly specific evidence of myocardial cell death. This finding typically means 1 of 2 scenarios. Elevations are indicative of an unstable coronary plaque that has produced brief coronary thrombosis or distal arterial microemboli. This may foreshadow subsequent complete coronary occlusion and is therefore treated aggressively with antiplatelet therapy. Cardiac enzyme elevation in the context of renal insufficiency, CHF, or severe noncardiac illness, is sometimes considered the result of secondary myocardial cell death. Although this finding indicates an increased likelihood of adverse events, it may signify myocardial stress but not unstable plaque.

• Troponin I levels of 0.4 ng/mL or higher or troponin T levels of 0.1 ng/mL or higher are considered positive and have been associated with higher short-term and midterm mortality. More importantly, outcomes in patients with troponin-positive results have been shown to be improved by aggressive treatment strategies that include an early cardiac catheterization strategy or use of IV glycoprotein IIb/IIIa platelet receptor antagonists.

• The temporal trends of these assays are helpful in interpreting difficult cases, and mild elevations of CK-MB or troponins from a lower baseline with subsequent falls in levels strongly indicate the occurrence of myonecrosis. Troponin levels also may still capture evidence of a cardiac event in patients who delay their presentation to the hospital because its serum half-life is longer than that of CK-MB and can remain elevated for 7-14 days after an event.

• On the other hand, once elevated, cardiac troponins are no longer useful in evaluating recurrent chest pain with myocardial injury, whereas CK-MB permits detection of reinfarction.

• Qualitative bedside troponin assay results may be difficult to interpret in patients with renal insufficiency.

• Clinical tip: Besides the ECG findings, troponin levels are now a centerpiece for diagnosis and prognostication in cases of unstable angina. Two sets of troponin results obtained 6-8 hours apart rules out NQMI but only if no new symptoms or ECG change has occurred since the last blood draw.

• Brain natriuretic peptide (BNP)

• A TACTICS/TIMI 18 substudy showed that BNP is an independent predictor of short- and long-term mortality and risk of CHF in patients presenting with unstable angina.

• Elevated BNP levels have also been linked to more significant coronary artery lesions in patients with unstable angina, including greater LAD involvement.

• BNP levels may add incremental information to the assessment of patients with unstable angina but should be used in context with other cardiac markers to guide medical decision making. The cost effectiveness of routine use of multiple cardiac biomarkers has not been established.

• C-reactive protein (CRP)

• Elevated serum CRP levels on admission indicate worse short- and long-term mortality in patients with unstable angina.

• Patients with elevated CRP levels at time of discharge are at greater risk for recurrent MI.

• In the absence of other inflammatory states, high-sensitivity CRP determination can refine risk stratification of patients with unstable angina. The TIMI 11A substudy showed that even for patients with a negative troponin test result, elevated CRP levels portend a higher mortality rate than that of patients in whom both troponin and CRP are negative (5.8% vs 0.36).

• CRP may add incremental information to cardiac enzymes but its role in medical decision-making in the acute setting remains unclear.

Imaging Studies:

• Perform chest radiography to evaluate patients for signs of CHF and for other causes of chest symptoms such as pneumothorax, pulmonary infection or masses, pulmonary hypertension, and mediastinal widening.

• If available on a prompt basis, echocardiography can provide a quick evaluation of left ventricular function for prognosis (worse when LVEF is <40%) or for diagnosis, such as when new segmental wall motion abnormality is detected (eg, in postinfarction or postrevascularization chest pain in which baseline left ventricular function is known). However, keep in mind that small infarcts may not be manifest on the echocardiogram.

• Important causes of chest pain, such as aortic stenosis and HOCM, can be readily detected by echocardiography.

• Transesophageal echocardiography, CT angiography (CTA), or magnetic resonance angiography (MRA) is invaluable when aortic dissection is being ruled out.

• MRI has emerging applications for identifying ischemia (space-time maps of impaired blood arrival), infarction (wall thinning, scar, delayed enhancement), and wall motion abnormalities that may be coupled with coronary artery assessment with MRA in the future.

• Clinical tip: TEE is highly recommended if the clinical picture suggests the possibility of a valvular or mechanical complication of MI, or for patients who are not following the expected hospital course.

Other Tests:

• Exercise testing is not typically performed in the acute phase of unstable angina or in subjects with recent rest angina. However, subjects in whom disease activity becomes controlled after several days of medical therapy may safely undergo stress testing before hospital discharge.

• When feasible, predischarge testing is preferential to testing weeks to months following discharge because no prognostic value is lost with early testing, and because a relatively high proportion of adverse cardiac events occur earlier rather than later.

• Predischarge exercise tests add independent prognostic information to known important clinical descriptors such as recurrent rest pain and evolutionary T wave changes. For example, patients who had a reversible defect on nuclear stress testing had a 25% incidence of death or MI at 1 year compared to only 2% for those with a negative scan. Among men, shorter exercise duration, lower maximal rate-pressure product, and exercise-induced angina or ST-segment depression have correlated with unfavorable outcome.

• Although the negative predictive value is on the order of 90% across the board for all modalities of stress tests, the positive predictive value is poor (16-19%) for exercise or adenosine stress tests and only moderately better for the imaging stress tests (31-48%).

• Many chest pain centers are evaluating the strategy of early stress testing to triage low-risk patients expeditiously. The Emergency Room Assessment of Sestamibi for Evaluation of Chest Pain (ERASE Chest Pain) randomized clinical trial compared usual care versus usual care plus a resting perfusion scan in patients with normal or nondiagnostic ECG for ischemia. The study showed a 32% reduction in the odds of being unnecessarily admitted to the hospital without sacrificing safety in patients without ischemia who underwent early nuclear perfusion scanning. Patients who have a moderate likelihood of CAD but are stratified to be at low risk for events probably can safely perform the exercise stress test at 6 hours.

• No large studies comparing the performance characteristics of the different stress-testing modalities in the specific setting of unstable angina are available.

Procedures:

• Electrocardiography

• The first line of assessment in any patient with suspected unstable angina is the 12-lead ECG, which should be obtained within 10 minutes of the patient's arrival at the emergency department. The diagnostic accuracy of an ECG is enhanced if a prior tracing is available for comparison.

• This allows detection of the highest-risk chest pain syndrome in patients who may in fact be in the midst of acute MI and thereby allows immediate triage to revascularization therapy. This is manifested by an ST elevation, new left bundle-branch block (LBBB), or peaked T wave (early)–type MI on ECG.

• The next level of high-risk patients includes those with ST depression greater than 1 mm on ECG; about half have subendocardial myocardial necrosis. In particular, ST depression carries relatively high in-hospital, 30-day, and 1-year mortality rates regardless of cardiac enzyme status, though the reason for this is unclear.

• New or reversible ST-segment deviation of 0.5 mm or more from baseline has been associated with a higher incidence (15.8% vs 8.2%) of 1-year death or MI in the TIMI-III Registry ECG Ancillary Study.

• Primary T wave changes are neither sensitive nor specific for ischemia, but they become an important clue in the context of symptoms or if the QRS–to–T wave angle is greater than 60°. Isolated symmetric T wave inversion does not appear to carry additional adverse prognosis.

• Clinical tip: The presence of ST-segment elevation or depression on ECG indicates high risk and must therefore be detected and acted on as soon as possible.

	TREATMENT	Section 6 of 11
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Medical Care: Because the course of unstable angina is highly variable and potentially life threatening, the aggressiveness of the course of unstable angina is highly variable and potentially life threatening, the aggressiveness of approach or level of care needs to be established expeditiously. The obvious goal of therapy is to reverse the oxygen supply-demand mismatch by minimizing requirements and maximizing delivery of tissue nutrients. Secondary or precipitating factors, such as anemia, hypoxemia, thyroid dysfunction, or febrile illness, should be sought and corrected.

Specific therapy for primary causes of ischemia should be directed at each pathophysiologic origin of unstable angina: increased myocardial rate-pressure product, coronary vasoconstriction, platelet aggregation, and thrombosis.

	MEDICATION	Section 7 of 11
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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Antiplatelet agents -- These agents prevent formation of thrombi associated with MI and inhibit platelet function by blocking aggregation. Antiplatelet therapy has been shown to reduce mortality by reducing the risk of fatal MIs, fatal strokes, and vascular death. Pooled data from over 2000 patients revealed reduction of death or MI from 11.8% to 6% with aspirin in cases of unstable angina. A recent randomized clinical trial involving 12,562 patients showed a reduction of cardiovascular death, MI, or stroke from 11.4% to 9.3% by adding clopidogrel to aspirin therapy.

Drug Name	Aspirin (Anacin, Bayer Buffered Aspirin, Ecotrin) -- Administer as soon as possible. Inhibits cyclo-oxygenase, which produces thromboxane A2, a potent platelet activator. Early administration has been shown to reduce mortality.
Adult Dose	160-324 mg PO qd
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; liver damage; hypoprothrombinemia; vitamin K deficiency; bleeding disorders; asthma; patients <16 y with influenza (because of association of aspirin with Reye syndrome)
Interactions	Effects may decrease with antacids and urinary alkalinizers; corticosteroids decrease salicylate serum levels; additive hypoprothrombinemic effects and increased bleeding time may occur with coadministration of anticoagulants; may antagonize uricosuric effects of probenecid and increase toxicity of phenytoin and valproic acid; doses >2 g/d may potentiate glucose-lowering effect of sulfonylurea drugs
Pregnancy	D - Unsafe in pregnancy
Precautions	May cause transient decrease in renal function and aggravate chronic renal disease; avoid use in patients with severe anemia, those with history of blood coagulation defects, or those taking anticoagulants

Drug Name	Clopidogrel (Plavix) -- Selectively inhibits adenosine diphosphate (ADP) binding to platelet receptor and subsequent ADP-mediated activation of glycoprotein llb/llla complex, thereby inhibiting platelet aggregation. This agent is used as an alternative to aspirin or in addition to aspirin after coronary stenting [CAPRIE Steering Committee, 1996 #158]. The recently concluded randomized clinical trial Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) showed an absolute risk reduction in cardiac death, MI, or stroke of 2.1% (11.4% down to 9.3% at 1-y) at the cost of increased major bleeding by 1.0% (3.7% versus 2.7%).
Adult Dose	CURE protocol for unstable angina patients within 24 h of symptom onset: 300 mg loading dose PO followed by 75 mg PO qd for 3-12 mo (mean = 9 mo) in conjunction with aspirin 75-325 mg/d PO
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; active pathological bleeding, such as peptic ulcer, or intracranial hemorrhage
Interactions	Coadministration with naproxen is associated with increased occult GI blood loss; clopidogrel prolongs bleeding time; safety of coadministration with warfarin not established
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in patients at increased risk of bleeding from trauma, surgery, or other pathological conditions; caution in patients with lesions with propensity to bleed (eg, ulcers)

Drug Category: HMG-CoA reductase inhibitors -- Used to treat hypercholesterolemia. Highly efficacious and very well tolerated.

Drug Name	Atorvastatin (Lipitor) -- Can provide up to 60% reduction in LDL-C. Inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase), which in turn inhibits cholesterol synthesis and increases cholesterol metabolism. The half-life of atorvastatin and active metabolites is longer than that of all the other statins (ie, approximately 48 h compared to 3-4 h). The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) randomized clinical trial randomized 3086 patients with unstable angina to high-dose atorvastatin versus placebo. Therapy resulted in a reduction in the primary endpoint (ie, death, MI, resuscitated cardiac arrest, severe recurrent symptomatic ischemia) from 17.4% to 14.8% (P = .048) within a relatively short period of 4 mo. The benefit was mostly for recurrent symptomatic ischemia with objective evidence and requiring emergency rehospitalization (8.4% down to 6.2%, P = .02).
Adult Dose	10 mg PO qd in the evening; titrate to a maximum 80 mg/d prn MIRACL protocol: 80 mg PO qd commenced within 1-4 d after admission for unstable angina, continue for at least 16 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; significant hepatic impairment; pregnancy; breastfeeding
Interactions	Toxicity increases when coadministered with triazole antifungals, CNS depressants, macrolide antibiotics, and mibefradil; atorvastatin increases the action of anticoagulants and levothyroxine
Pregnancy	X - Contraindicated in pregnancy
Precautions	Thirty-one cases of rhabdomyolysis (out of 1.33 million total prescriptions) were reported in Canada, resulting in 1 death associated with concomitant use of gemfibrozil, a fibric acid derivative; concomitant use with nicotinic acid (niacin) also advised Stop drug use or decrease doses for elevations of transaminases more than 3 times the upper limit of the reference range; elevations generally resolve upon withdrawal of drug; if symptoms of myopathy and rhabdomyolysis occur, stop the drug and obtain a CK Do not exceed daily dose; caution in patients receiving drugs that prolong QRS or Q-T interval; monitor transaminase levels before treatment, at 6 wk and 12 wk, then q6mo

Drug Category: Glycoprotein IIb/IIIa receptor antagonists -- Up to 80,000 copies of these integrins on the platelet cell surface serve as ligands for fibrinogen cross-linkage, the final common pathway for platelet aggregation and thrombus formation, even under arterial shear stress conditions. To date, more than 40,000 patients have been enrolled in randomized clinical trials evaluating glycoprotein IIb/IIIa antagonists in ACS. These trials have shown 30-day relative risk reductions of 22–56% in composite end points, with beneficial trends in each of the component outcomes, largely in association with percutaneous coronary intervention.

Drug Name	Tirofiban (Aggrastat) -- Nonpeptide antagonist of platelet GP IIb/IIIa receptor that reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. Effects persist over the duration of maintenance infusion and are reversed after stopping the infusion. Approved by the FDA for use in combination with heparin for patients with ACS who are being managed medically and for those undergoing PCI. Dose should be halved in patients with severe renal insufficiency (CrCl <30 mL/min).
Adult Dose	0.4 mcg/kg/min IV for 30 min, followed by 0.1 mcg/kg/min for up to 72 h If CrCl <30 mL/min, then reduce dose by 50%
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe hypertension (systolic BP >200 mm Hg); active internal bleeding; history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm; acute pericarditis; bleeding diathesis; trauma or stroke within previous 30 d; platelet count <100,000/mm3; history of thrombocytopenia following exposure to this product; serum creatinine >2 mg/dL (for 180 mcg/kg bolus and 2 mcg/kg/min infusion) or >4 mg/dL (for 135 mcg/kg bolus and 0.5 mcg/kg/min infusion); history of bleeding diathesis within 30 d; intracranial hemorrhage; history of hemorrhagic stroke; severe hypertension (systolic BP >200 mm Hg or diastolic BP >110 mm Hg); major surgical procedure within past mo
Interactions	Possible increased risk of bleeding with coadministration of heparin or aspirin; closely monitor when using concurrently with drugs that affect hemostasis (eg, warfarin)
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Bleeding events are the most common complications encountered during therapy with eptifibatide; caution with platelet count <150,000/mm3 and hemorrhagic retinopathy; prior to treatment, monitor platelet counts, serum creatinine, hemoglobin, hematocrit, and PT/aPTT within 6 h after loading infusion and at least daily thereafter (more frequently if evidence of significant decline); because these agents inhibit platelet aggregation, caution when using concurrently with drugs that affect hemostasis (eg, thrombolytics, ticlopidine, NSAIDs, warfarin, dipyridamole, clopidogrel); measure ACT and maintain aPTT 50-70 seconds unless a PCI needs to be performed; maintain ACT 300-350 seconds during PCI; if platelet count decreases to <100,000/mm3, perform additional platelet counts to exclude pseudothrombocytopenia; if thrombocytopenia is confirmed, discontinue GP IIb/IIIa inhibitors and heparin and appropriately monitor and treat the condition; to monitor unfractionated heparin, monitor aPTT 6 h after beginning heparin infusion; adjust to maintain aPTT higher than 2 times baseline

Drug Name	Eptifibatide (Integrilin) -- Cyclic heptapeptide antagonist of the platelet GP IIb/IIIa receptor that reversibly prevents von Willebrand factor, fibrinogen, and other adhesion ligands from binding to the GP IIb/IIIa receptor, thereby inhibiting platelet aggregation. Effects persist over duration of maintenance infusion and are reversed when infusion ends. Approved by the FDA for use in combination with heparin for patients with ACS, patients who are being managed medically, and for those undergoing PCI.
Adult Dose	Unstable angina: 180 mcg/kg IV bolus, followed by continuous infusion of 2 mcg/kg/min for up to 72 h Undergoing PCI: Additional 180 mcg/kg IV bolus 10 min after the first bolus For patients with serum Cr >2 mg/dL: Lower dose to 135 mcg/kg bolus and 0.5 mcg/kg/min infusion
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe hypertension (systolic BP >200 mm Hg); active internal bleeding; history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation or aneurysm, acute pericarditis, or bleeding diathesis; trauma or stroke within previous 30 d; platelet count <100,000/mm3; history of thrombocytopenia following prior exposure to this product; serum Cr >4 mg/dL
Interactions	Possible increased risk of bleeding with coadministration of heparin, warfarin, or aspirin; closely monitor when using other drugs that affect hemostasis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Bleeding events are the most common complications encountered during therapy with eptifibatide; caution in platelet count <150,000/mm3 and hemorrhagic retinopathy; because agent inhibits platelet aggregation, caution when using concurrently with drugs that affect hemostasis (eg, thrombolytics, ticlopidine, NSAIDs, warfarin, dipyridamole, clopidogrel); measure ACT and maintain aPTT 50-70 seconds unless a PCI needs to be performed; maintain ACT 250-350 seconds during a PCI; if platelets decrease to <100,000/mm3, perform additional platelet counts to exclude possibility of pseudothrombocytopenia; if thrombocytopenia is confirmed, discontinue GP IIb/IIIa inhibitors and heparin and appropriately monitor and treat the condition; monitor aPTT 6 h after start of heparin infusion and at least daily thereafter

Drug Category: Platelet aggregation inhibitors -- Inhibit platelet aggregation.

Drug Name	Abciximab (ReoPro) -- Chimeric human-murine monoclonal antibody approved for use in elective/urgent/emergent PCI. Binds to receptor with high affinity and reduces platelet aggregation by 80% for up to 48 h following infusion. The recently concluded GUSTO-4 randomized clinical trial did not show any benefit for abciximab in medically treated patients who do not undergo PCI. In fact, longer duration of abciximab use was associated with a negative trend in event rates. On the other hand, in the context of PCI, it has been shown to be superior to tirofiban.
Adult Dose	0.25 mg/kg IV bolus, followed by 10 mcg/min IV for 12 h after PCI
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; severe hypertension (systolic BP >200 mm Hg); active internal bleeding; history of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation or aneurysm, acute pericarditis, or bleeding diathesis; trauma or stroke within previous 30 d; platelet count <100,000/mm3; history of thrombocytopenia following prior exposure to this product
Interactions	Possible increased risk of bleeding with coadministration with heparin, warfarin, or aspirin; closely monitor when using other drugs that affect hemostasis
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Bleeding events are the most common complications encountered during therapy with abciximab; caution in platelet count <150,000/mm3 and hemorrhagic retinopathy; because agent inhibits platelet aggregation, caution when using concurrently with drugs that affect hemostasis (eg, thrombolytics, ticlopidine, NSAIDs, warfarin, dipyridamole, clopidogrel); measure ACT and maintain aPTT 50-70 seconds unless a PCI needs to be performed; maintain ACT 250-350 seconds during a PCI; if platelets decrease to <100,000/mm3, perform additional platelet counts to exclude possibility of pseudothrombocytopenia; if thrombocytopenia is confirmed, discontinue GP IIb/IIIa inhibitors and heparin and appropriately monitor and treat condition; monitor aPTT 6 h after start of heparin infusion and at least daily thereafter; abciximab is associated with an incidence of thrombocytopenia in approximately 2% of patients

Drug Category: Beta-adrenergic blocking agents -- Limit heart rate and reduce blood pressure to decrease myocardial oxygen demand, oppose effects of elevated catecholamines, and produce antiarrhythmic properties. Clinical trials of beta-adrenoreceptor blockers in cases of unstable angina have shown decreases in ischemic symptoms and in occurrence of MIs. In vitro studies have shown inhibition of platelet aggregation with this drug class. Infrequent situations in which beta-blocker therapy should be avoided in patients with unstable angina include nonischemic exacerbation of heart failure, cocaine-induced coronary vasoconstriction, and vasospastic angina.

Drug Name	Metoprolol (Lopressor, Toprol XL) -- Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. During IV administration, carefully monitor blood pressure, heart rate, and ECG.
Adult Dose	5 mg IV slow infusion q5min up to 3 times until resolution of angina or titrate to reduce heart rate to 50-70 bpm
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncompensated congestive heart failure; bradycardia; asthma; cardiogenic shock; AV conduction abnormalities
Interactions	Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels of metoprolol, possibly resulting in decreased pharmacologic effects; toxicity of metoprolol may increase with coadministration of sparfloxacin, phenothiazines, astemizole, calcium channel blockers, quinidine, flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; closely monitor patient and slowly withdraw the drug; caution in patients taking other negative chronotropes or inotropes (eg, verapamil)

Drug Name	Esmolol (Brevibloc) -- Shown to reduce episodes of chest pain and clinical cardiac events compared to placebo. The very short half-life (8 min) allows a large degree of dosing flexibility, such that cardiovascular benefits are comparable to PO propranolol, yet adverse effects can be managed promptly. It is particularly useful for patients at risk for complications with beta-blockade (eg, reactive airway disease or COPD, severe bradycardia, or poor left ventricular function).
Adult Dose	0.05 mg/kg/min IV over 1 min initially; 0.1 mg/kg/min IV maintenance; titrate in increments of 0.05 mg/kg/min q10-15min until resolution of angina, until heart rate of 50-70 bpm is attained, or until maximum dose of 0.2 mg/kg/min is reached
Pediatric Dose	Not established
Contraindications	Documented hypersensiti