Acute Coronary Syndromes Without ST-Segment Elevation

For further information, see CMDT Part 10-23: Acute Coronary Syndromes Without ST-Segment Elevation

Essentials of Diagnosis

• Distinction in acute coronary syndrome (ACS) between patients with and without ST-segment elevation at presentation is essential to determine need for reperfusion therapy

• Fibrinolytic therapy is harmful in ACS without ST-segment elevation, unlike with ST-segment elevation where acute reperfusion saves lives

• Antiplatelet and anticoagulation therapies and coronary intervention are mainstays of treatment

General Considerations

• Acute coronary syndromes comprise the spectrum of unstable cardiac ischemia from unstable angina to myocardial infarction (MI)

• Acute coronary syndromes are classified based on the presenting ECG as either "ST-segment elevation" (STEMI) or "non–ST-segment elevation"

• The evolution of cardiac biomarkers allows determination of whether MI has occurred

• The universal definition of myocardial infarction is a rise of cardiac biomarkers with at least one value above the 99th percentile of the upper reference limit together with evidence of myocardial ischemia with at least one of the following:

  • Symptoms of ischemia

  • ECG changes of new ischemia

  • New Q waves

  • Imaging evidence of new loss of viable myocardium or new wall motion abnormality

• Acute coronary syndromes represent a dynamic state in which patients frequently shift from one category to another, as new ST elevation can develop after presentation and cardiac biomarkers can become abnormal with recurrent ischemic episodes

Symptoms and Signs

• Angina occurs at rest or with minimal exertion

• Substernal chest pain or discomfort that may radiate to the jaw, left shoulder, or arm

• Dyspnea, nausea, diaphoresis or syncope may either accompany the chest discomfort or may be the only symptom of ACS

• About one-third of patients with MI have no chest pain per se—these patients tend to be older, female, have diabetes, and be at higher risk for subsequent mortality

• Patients with ACS have signs of heart failure in about 10% of cases, and this is also associated with higher risk of death

Differential Diagnosis

• MI with ST-segment elevation

• Aortic dissection

• Pulmonary embolism

• Tension pneumothorax

• Pericarditis

• Esophageal rupture

• Stress cardiomyopathy (Tako-Tsubo cardiomyopathy or apical ballooning syndrome)

Laboratory Tests

• Depending on the time from symptom onset to presentation, initial laboratory findings may be normal

• Cardiac myocyte necrosis, myoglobin, creatine kinase (CK)-MB, and troponin I and T may all be used to identify acute MI

  • In patients with STEMI, these initial markers are often within normal limits as the patient is being rushed to immediate reperfusion

  • In patients without ST-segment elevation, it is the presence of abnormal CK-MB or troponin values that are associated with myocyte necrosis and the diagnosis of MI

• High-sensitivity troponin assays allow rapid sex-based rule out algorithms for MI in emergency departments

• Serum creatinine is an important determinant of risk

• Estimated creatinine clearance is important to guide dosing of certain antithrombotics, including eptifibatide and enoxaparin

Diagnostic Studies

• ECG changes

  • ST-segment elevation, ST-segment depression, or T wave flattening or inversion may be seen in patients with pain

  • Dynamic ST-segment shift is the most specific for ACS

  • ST-segment elevation in lead aVR suggests left main or three vessel disease

Treatment

• Indications for invasive strategies are shown in Table 10–9

• Hospitalization, bed rest, telemetry, and supplemental oxygen

• Cardiology consultation

Medications

• Patients should receive a combination of antiplatelet and anticoagulant agents on presentation

  • ACC/AHA guidelines call for a P2Y₁₂ inhibitor (clopidogrel, prasugrel [at the time of PCI], or ticagrelor)

  • European Society of Cardiology guidelines call for P2Y₁₂ inhibitor upfront

  • Both sets of guidelines recommend postponing elective CABG surgery for at least 5 days after the last dose of clopidogrel or ticagrelor and at least 7 days after the last dose of prasugrel due to risk of bleeding

• Fibrinolytic therapy should be avoided in patients without ST-segment elevation

• Antiplatelet therapy

  • Aspirin (first-line therapy): 81–325 mg orally immediately and then once daily for the first month; 75–162 mg/day preferred over high doses for longer-term treatment

  • P2Y₁₂ inhibitors

    • Ticagrelor recommended for all patients at moderate to high risk for ACS (class 1 recommendation)

    • Prasugrel for patients who have not yet received another P2Y₁₂ inhibitor, for whom a PCI is planned, and who are not at high risk for life-threatening bleeding

    • Clopidogrel is reserved for patients who cannot receive either ticagrelor or prasugrel

      • Clopidogrel: 300 mg oral loading dose, then 75 mg/day for 9–12 months, sometimes added

      • "Double-dose" clopidogrel (600 mg initial oral loading dose, followed by 150 mg orally daily) for 7 days is an option for patients with ACS undergoing PCI

  • Glycoprotein IIb/IIIa inhibitors

    • Useful adjuncts in high-risk patients (usually defined by fluctuating ST-segment depression or positive biomarkers) with ACS, particularly when they are undergoing PCI

    • Tirofiban, 0.4 mcg/kg/min for 30 minutes, followed by 0.1 mcg/kg/min, or eptifibatide, 180 mcg/kg bolus followed by a continuous infusion of 2 mcg/kg/min, are effective

      • Downward dose adjustments (1 mcg/kg/min) are required in patients with reduced kidney function (eg, if the estimated creatinine clearance is below 50 mL/min, the eptifibatide infusion should be cut in half to 1 mcg/kg/min)

        • Eptifibatide started at the time of admission has no benefit and has higher rates of bleeding compared with eptifibatide treatment started at the time of invasive coronary angiography

        • Intravenous abciximab (added to clopidogrel 600 mg loading dose) reduces ischemic events by about 25% for patients undergoing PCI with high-risk ACS, especially with elevated troponin

• Anticoagulant therapy

  • Heparin

    • Low-molecular-weight heparin: eg, enoxaparin 1 mg/kg every 12 hours subcutaneously, somewhat superior to unfractionated heparin in several trials

    • SYNERGY trial, however, showed that unfractionated heparin and enoxaparin had similar rates of death or (re)infarction in the setting of frequent early coronary intervention

  • Fondaparinux, 2.5 mg subcutaneously once a day

    • Equally effective as enoxaparin among 20,000 patients at preventing early death, MI, and refractory ischemia

    • Resulted in a 50% reduction in major bleeding

    • Especially favorable for patients initially treated medically and who are at high risk for bleeding, such as the elderly

    • Catheter-related thrombosis, more common during intervention procedures with fondaparinux, can be controlled by adding unfractionated heparin (85 units/kg without glycoprotein IIb/IIIa inhibitors, and 60 units/kg with glycoprotein IIb/IIIa inhibitors) during procedure

  • Direct thrombin inhibitors

    • Bivalirudin is alternative to heparin (unfractionated heparin or enoxaparin) plus a glycoprotein IIb/IIIa antagonist for many patients with ACS who are undergoing early coronary intervention

      • Bivalirudin (without routine glycoprotein IIb/IIIa inhibitor) is associated with substantially less bleeding than heparin plus glycoprotein IIb/IIIa inhibitor, although may have numerically increased cardiovascular events

      • The ISAR REACT-4 trial showed that bivalirudin has similar efficacy to abciximab but better bleeding outcomes

• Nitroglycerin (first-line therapy): sublingual, oral, or topical initially, but continuous drip if pain persists or recurs

  • Start at 10 mcg/min, titrate upward by 10–20 mcg/min (to a maximum of 200 mcg/min)

  • Continuous blood pressure monitoring required

• β-Blockers (first-line therapy): orally or intravenously for more rapid effect

  • For example, metoprolol 5-mg intravenous doses × 3 at 5-min intervals, unless overt heart failure

  • Oral therapy titrated upward as tolerated by blood pressure

• Reduce systolic blood pressure to 100–120 mm Hg with nitroglycerin and β-blockers, except in patients with history of severe hypertension

• Calcium channel blockers

  • Not shown to favorably affect outcome in unstable angina

  • Should be used primarily as third-line therapy in patients with continuing angina on nitrates and β-blockers or those who are not candidates for these drugs

  • In the presence of nitrates and without accompanying β-blockers, diltiazem or verapamil is preferred, since nifedipine and the other dihydropyridines are more likely to cause reflex tachycardia or hypotension

  • Use low initial dosage, but upward titration should proceed steadily (see Table 11–7)

• Benzodiazepine sedation if anxiety is present

• Statins

  • Should be started in the days immediately following an ACS

  • High-dose statins are recommended for all patients with acute coronary syndromes

  • More intensive therapy with atorvastatin 80 mg/day, regardless of total or LDL cholesterol level, improves outcome compared to pravastatin 40 mg/day

Temporary Discontinuation of Antiplatelet Therapy for Procedures

• If possible, procedures (eg, dental procedures or colonoscopy) should be delayed until the end of the necessary treatment period with P2Y₁₂ inhibitors, which generally is at least 1 month with bare metal stents and 3–6 months with drug-eluting stents

• With newer generation drug-eluting stents, patients with bleeding risk who are undergoing elective stenting may have their P2Y₁₂ inhibitors stopped before 3 months

• Before that time, if a procedure is necessary, risk and benefit of continuing the antiplatelet therapy to prevent stent thrombosis through the time of the procedure should be assessed

• Aspirin should generally be continued throughout the period of the procedure

• Patients with polymer-free drug coated stents who are at high risk for bleeding and receiving a short course of dual antiplatelet therapy have fewer cardiovascular and bleeding events than patients with bare metal stents

• Consult a cardiologist before temporary discontinuation of these agents

Therapeutic Procedures

• Indications for coronary angiography

  • For patients with ACS, including non–ST-segment elevation MI, risk stratification is important for determining intensity of care

  • Several therapies, including glycoprotein IIb/IIIa inhibitors, low-molecular-weight heparin, and early invasive catheterization, have been shown to have the greatest benefit in higher-risk patients with ACS

  • As outlined in the ACC/AHA guidelines, patients with any high-risk feature generally warrant an early invasive strategy with catheterization and revascularization

  • For patients without these high-risk features, either an invasive or noninvasive approach, using exercise or pharmacologic stress testing to identify patients who have residual ischemia or high risk can be used

  • Moreover, a strategy based on selective coronary angiography and revascularization for instability or inducible ischemia, or both, is acceptable (ACC/AHA class IIb recommendation)

When to Refer

• All patients with acute MI should be referred to a cardiologist

• Patients who are taking a P2Y₁₂ inhibitor following coronary stenting should consult a cardiologist before discontinuing treatment for nonemergency procedures