Acute Coronary Syndromes, Unstable Angina, and Non–ST-Segment Elevation Myocardial Infarction

General Principles

Definition

  • NSTEMI and UA are closely related conditions whose pathogenesis and clinical presentations are similar but differ in severity.
  • If coronary flow is not severe enough or the occlusion does not persist long enough to cause myocardial necrosis (as indicated by positive cardiac biomarkers), the syndrome is labeled UA.
  • NSTEMI is defined by an elevation of cardiac biomarkers and the absence of ST-segment elevation on the ECG.
  • NSTEMI, like STEMI, can lead to cardiogenic shock.
  • AHA/ACC guidelines provide a more thorough overview of NSTEMI/UA.1

Epidemiology

  • The annual incidence of acute coronary syndrome (ACS) is >780,000 events, with 70% being NSTEMI/UA.
  • Among patients with ACS, approximately 60% have UA and 40% have MI (one-third of MIs present with an acute STEMI).
  • At 1 year, patients with UA/NSTEMI are at considerable risk for death (∼6%), recurrent MI (∼11%), and need for revascularization (∼50%–60%). It is important to note that although the short-term mortality of STEMI is greater than that of NSTEMI, the long-term mortality is similar.1
  • Patients with NSTEMI/UA tend to have more comorbidities, both cardiac and noncardiac, than STEMI patients.
  • Women with NSTEMI/UA have worse short-term and long-term outcomes and more complications compared to men. Much of this has been attributed to delays in recognition of symptoms and underutilization of guideline-directed medical therapy and invasive management.2

Etiology and Pathophysiology

  • Myocardial ischemia results from decreased myocardial oxygen supply and/or increased demand. In the majority of cases, NSTEMI is due to a sudden decrease in blood supply via partial occlusion of the affected vessel. In some cases, markedly increased myocardial oxygen demand may lead to NSTEMI (demand ischemia), as seen in severe anemia, hypertensive crisis, acute decompensated HF, surgery, or any other significant physiologic stressor.
  • UA/NSTEMI most often represents severe coronary artery narrowing or acute atherosclerotic plaque rupture/erosion and superimposed thrombus formation. Alternatively, it may also be due to progressive mechanical obstruction from advancing atherosclerotic disease, in-stent restenosis, or bypass graft disease.
  • Plaque rupture may be triggered by local and/or systemic inflammation as well as shear stress. Rupture allows exposure of lipid-rich subendothelial components to circulating platelets and inflammatory cells, serving as a potent substrate for thrombus formation. A thin fibrous cap (thin-cap fibroatheroma) is felt to be more vulnerable to rupture and is most frequently represented as only moderate stenosis on angiography.
  • Less common causes include dynamic obstruction of the coronary artery due to vasospasm (Prinzmetal angina, cocaine), coronary artery dissection (more common in women), coronary vasculitis, and embolus.

Diagnosis

Clinical Presentation

History

  • ACS symptoms include all the qualities of typical angina except the episodes are more severe, of longer duration, and may occur at rest.
  • The three principal presentations for UA are rest angina (angina occurring at rest and prolonged, usually >20 minutes), new-onset angina, and progressive angina (previously diagnosed angina that has become more frequent, lasts longer, or occurs with less exertion). New-onset and progressive angina should occur with at least mild to moderate activity, CCS class III severity.
    • Female sex, diabetes, HF, end-stage kidney disease, and older age are traits that have been associated with a greater likelihood of atypical ACS symptoms. However, the most common presentation in these populations is still typical anginal chest pain.
    • Jaw, neck, arm, back, or epigastric pain and/or dyspnea can be anginal equivalents.
    • Pleuritic pain, pain that radiates down the legs or originates in the mid/lower abdomen, pain that can be reproduced by extremity movement or palpation, and pain that lasts seconds in duration are unlikely to be related to ACS.

Physical Examination

  • Physical examination should be directed at identifying hemodynamic instability, pulmonary congestion, and other causes of acute chest discomfort.
  • Objective evidence of HF including peripheral hypoperfusion, heart murmur (particularly MR murmur), elevated jugular venous pulsation, pulmonary edema, hypotension, and peripheral edema worsens the prognosis.
  • Killip classification can be useful to risk stratify and identify patients with features of cardiogenic shock (Table 4-11).
    Table 4-11: Killip Classification
    ClassDefinitionMortalitya
    INo signs or symptoms of heart failure6%
    IIHeart failure: S3 gallop, rales, or JVD17%
    IIISevere heart failure: pulmonary edema38%
    IVCardiogenic shock: SBP <90 mm Hg and signs of hypoperfusion and/or signs of severe heart failure81%

    aIn-hospital mortality of patients in 1965–1967 with no reperfusion therapy (n = 250).3

    JDV, jugular venous distention; SBP, systolic blood pressure.

  • Examination may also give clues to other causes of ischemia such as thyrotoxicosis or aortic dissection (see Table 4-4).

Diagnostic Testing

Electrocardiography

  • Before or immediately on arrival to the emergency department, a baseline ECG should be obtained in all patients with suspected ACS. A normal tracing does not exclude the presence of disease.
  • The presence of Q waves, ST-segment changes, or T-wave inversions is suggestive of CAD.
  • Isolated Q waves in lead III only are a normal finding.
  • Serial ECGs should be obtained to assess for dynamic ischemic changes.
  • Comparison to prior ECGs is important when evaluating an ECG for dynamic changes.
  • The posterior circulation (i.e., circumflex coronary artery distribution) is poorly assessed with standard ECG lead placement and should always be considered when evaluating patients with ACS. Posterior placed leads or urgent echocardiography may more accurately assess the presence of ischemia when the suspicion is high.
  • Approximately 50% of patients with UA/NSTEMI have significant ECG abnormalities, including transient ST-segment elevations, ST depressions, and T-wave inversions.1
    • ST-segment depression in two contiguous leads is a sensitive indicator of myocardial ischemia, especially if dynamic and associated with symptoms.
      • The threshold value for abnormal J-point depression should be 0.5 mm in leads V2 and V3 and 1 mm in all other leads.
      • ST-segment depression in multiple leads plus ST-segment elevation in aVR and/or V1 suggests ischemia due to multivessel or left main disease.
    • Biphasic or deeply inverted T waves (>5 mm) with QT prolongation in leads V2 to V4 in the setting of stuttering chest pain within the past 24 hours suggests a critical lesion in the LAD artery distribution (Wellens Syndrome).4
    • Nonspecific ST-segment changes or T-wave inversions (those that do not meet voltage criteria) are nondiagnostic and unhelpful in the management of acute ischemia but are associated with a higher risk for future cardiac events.

Laboratories

  • A complete blood count, basic metabolic panel, fasting glucose, and lipid profile should be obtained in all patients with suspected CAD. Other conditions may be found to be contributing to ischemia (e.g., anemia) or mimicking ischemia (e.g., hyperkalemia-related ECG changes) or may alter management (e.g., severe thrombocytopenia).
  • Cardiac biomarkers are essential in the diagnosis of UA/NSTEMI and should be obtained in all patients who present with chest discomfort suggestive of ACS.
  • Troponin is the recommended biomarker for assessment of myocardial necrosis.
    • Troponin T and I assays are highly specific and sensitive markers of myocardial necrosis. Serum troponin levels are usually undetectable in normal individuals, and any elevation is considered abnormal.
    • In patients with troponin below the detectable limit of the assay within 6 hours of the onset of pain, a second sample should be drawn 8–12 hours after symptom onset.
    • MI size and prognosis are directly proportional to the magnitude of increase in troponin.5,6
  • Creatine kinase (CK)-MB is no longer a recommended marker for the initial diagnosis of NSTEMI. It lacks specificity because it is present in both skeletal and cardiac muscle cells.
    • CK-MB may be a useful assay for detecting postinfarct ischemia because a fall and subsequent rise in enzyme levels suggests reinfarction if accompanied by recurrent ischemic symptoms or ECG changes.
  • Brain natriuretic peptide (BNP) can be a useful biomarker of myocardial stress in patients with ACS, and elevations are associated with worse outcomes. Severe elevations of BNP in the setting of ACS in patients without known HF should raise concern for a large infarction and urgent angiography.7

Treatment

  • Acute treatment aims to reduce the symptoms of chest pain and risks of recurrent MI or death.
  • Risk stratification can be helpful in determining the appropriate testing, pharmacologic interventions, and timing or need for coronary angiography.
    • Risk of death or MI progression is elevated with the following high-risk ACS characteristics, which should prompt urgent coronary angiography (<2 hours) with the intent to revascularize:
      • Recurrent/accelerating angina despite adequate medical therapy
      • Signs or symptoms of new HF, pulmonary edema, or shock (high Killip Classification)
      • New or worsening MR
      • New LBBB
      • VT
    • Several clinical tools can estimate a patient’s risk of recurrent MI and cardiac mortality, such as the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) risk scores. The TIMI risk score can be used to determine the risk of death or nonfatal MI up to 1 year after an ACS event (Figure 4-2).
      Figure 4-2 Fourteen-day rates of death, MI, or urgent revascularization from the TIMI 11B and ESSENCE trials based on increasing TIMI risk score.
      Descriptive text is not available for this image

      Coronary artery disease (CAD) risk factors include family history of CAD, diabetes, hypertension, hyperlipidemia, and tobacco use. ASA, aspirin; LMWH, low–molecular-weight heparin; MI, myocardial infarction; TIMI, Thrombolysis in Myocardial Infarction; UFH, unfractionated heparin.8

  • In the stabilized patient, two treatment strategies are available: the ischemia-driven approach (formerly termed conservative) versus the routine invasive approach (early defined as <24 hours of presentation or delayed >24 hours).
    • The planned approach should always be individualized to the patient (Figure 4-3). All patients should receive aggressive antithrombotic, antiplatelet, and ischemic medical therapy no matter the final revascularization strategy. Table 4-12 summarizes the selection approach.
      Figure 4-3 Diagnostic and therapeutic approach to patients presenting with acute coronary syndrome (ACS) focusing on antiplatelet and antithrombotic therapy.
      Descriptive text is not available for this image

      *Bivalirudin is an appropriate alternative to UFH and LMWH, or at time of PCI, patients on UFH may be switched to bivalirudin. †Choose either clopidogrel, ticagrelor, or prasugrel as the second antiplatelet agent. #Indicators of recurrent ischemia include worsening chest pain, increasing cardiac biomarkers, heart failure signs/symptoms, arrhythmia (VT/VF), and dynamic ECG changes. ASA, aspirin; CABG, coronary artery bypass grafting; CAD, coronary artery disease; EF, ejection fraction; glycoprotein IIb/IIIa inhibitor; LMWH, low–molecular-weight heparin; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; Rx, treatment; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina; UFH, unfractionated heparin; VT/VF, ventricular tachycardia/ventricular fibrillation; WMA, wall motion abnormality.1,9

      Table 4-12: Appropriate Selection of Routine Invasive Versus Ischemia-Driven Revascularization Strategy in Patients With NSTEMI/UA
      Immediate/urgent invasive (within 2 h)Refractory angina
      Worsening signs or symptoms of heart failure or mitral regurgitation
      Hemodynamic instability or shock
      Sustained VT or VF
      Ischemia-drivenLow-risk score (TIMI ≤1 or GRACE <109)
      Low-risk biomarker-negative female patients
      Patient or clinician preference in the absence of high-risk features
      Early invasive (within 24 h)None of the above but a high-risk score (TIMI ≥3 or GRACE >140)
      Rapid rate of rise in biomarkers
      New or presumably new ST depressions
      Delayed invasive (24–72 h)None of the above but presence of diabetes
      Renal insufficiency (GFR <60)
      LV ejection fraction <40%
      Early postinfarction angina
      Prior PCI within 6 mo
      Prior CABG
      TIMI score ≥2 or GRACE score 109–140 and no indication for early invasive strategy

      CABG, coronary artery bypass graft; GFR, glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; LV, left ventricular; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; TIMI, Thrombolysis in Myocardial Infarction; UA, unstable angina; VF, ventricular fibrillation; VT, ventricular tachycardia.

    • In ACS, as opposed to stable IHD, a routine invasive approach with possible PCI has been shown to reduce the incidence of recurrent MI, hospitalizations, and death. In general, patients with ACS should undergo a routine invasive strategy unless it is clear that the risk outweighs the possible benefit in a given patient.
    • In the ischemia-driven approach, if the patient does not develop high-risk ACS features, has normal subsequent cardiac biomarkers, has no dynamic ECG changes, and responds to medical therapy, a noninvasive stress test should be obtained for further risk stratification.
      • Patients should be angina-free for at least 12 hours before stress testing.
      • If a patient with positive cardiac biomarkers is selected for noninvasive testing, a submaximal or pharmacologic stress test 72 hours after the peak value may be performed.
      • Coronary angiography is reserved for patients who develop high-risk ACS features, have a high-risk stress test, develop angina at low levels of stress, or are noted to have an LVEF <40%.
    • In the routine invasive strategy, the patient is planned for a coronary angiography with the intent to revascularize. An early (<24 hours from presentation) invasive approach is recommended for patients with high-risk scores or other high-risk features (see Table 4-12).
    • Refractory chest pain, hemodynamic instability, or serious ventricular arrhythmias are indications for an urgent/emergent invasive strategy similar to STEMI; this is not to be confused with a routine invasive strategy.
    • An early invasive strategy is also warranted in low- or intermediate-risk patients with repeated ACS presentations despite appropriate therapy.
    • A routine invasive strategy is not recommended for the following:
      • Patients with severe comorbid illnesses such as advanced CKD, end-stage liver or lung disease, or metastatic/uncontrolled cancer whereby the benefits of the procedure are likely outweighed by the risk from the routine invasive procedure.
      • Acute chest pain with a low likelihood of ACS and negative biomarkers, especially in women.

Medications

  • Patients presenting with UA/NSTEMI should receive medications that reduce myocardial ischemia through reduction in myocardial oxygen demand, improvement in coronary perfusion, and prevention of further thrombus formation.
  • This approach should include antiplatelet, anticoagulant, and antianginal medications.
  • Supplemental oxygen should be provided if the patient is hypoxemic (<90%) or having difficulty in breathing. Routine use of oxygen is not needed and possibly harmful.10,11
  • Antiplatelet therapy
    • Table 4-13 summarizes available agents and dosing recommendations for use in ACS.
      Table 4-13: Antiplatelet Agents in UA/NSTEMI
      MedicationDosageComments
      Aspirin (ASA)162–325 mg initial, then 75–100 mgIn patients taking ticagrelor, the maintenance dose of ASA should not exceed 100 mg.
      Clopidogrel300–600 mg loading dose, 75 mg dailyIn combination with ASA, clopidogrel (300–600 mg loading dose, then 75 mg/d) decreased the composite end point of cardiovascular death, MI, or stroke by 18%–30% in patients with UA/NSTEMI.12
      Ticagrelor180 mg loading dose, then 90 mg bidTicagrelor reduced incidence of vascular death, MI, or CVA (9.8% vs. 11.0%) but with higher major bleeding not related to CABG (4.5% vs. 3.8%) as compared to clopidogrel.13
      Prasugrel60 mg loading dose, 10 mg dailyPrasugrel has increased antiplatelet potency compared to clopidogrel.
      Prasugrel reduced the incidence of cardiovascular death, MI, and stroke (9.9% vs. 12.1%) at the expense of increased major (2.4% vs. 1.1%) and fatal bleeding (0.4% vs. 0.1%), compared to clopidogrel.14
      Cangrelor30 mcg/kg IV bolus, then 4 mcg/kg per minuteCurrently FDA approved only for patients undergoing PCI. Expense and modest evidence of benefit compared to other P2Y12 inhibitors limit use.
      Eptifibatide180 μg/kg IV bolus, 2 μg/kg per minuteaEptifibatide reduces the risk of death or MI in patients with ACS undergoing either invasive or noninvasive therapy in combination with ASA and heparin.15,16
      Compared to abciximab and tirofiban, eptifibatide has the most consistent effects on platelet inhibition with shortest on-time and drug half-life.17
      Tirofiban0.4 μg/kg IV bolus, 0.1 μg/kg per minuteaTirofiban reduces the risk of death or MI in patients with ACS undergoing either invasive or noninvasive therapy in combination with ASA and heparin.1
      Abciximab0.25 mg/kg IV bolus, 10 μg/minbAbciximab reduces the risk of death or MI in patients with ACS undergoing coronary intervention. It should not be used in patients in whom percutaneous intervention is not planned.1
      Platelet inhibition may be reversed by platelet transfusion.

      aInfusion doses should be decreased by 50% in patients with a GFR <30 mL/min and avoided in patients on HD.

      bAbciximab may be used in patients with ESRD because it is not cleared by the kidney.

      ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CVA, cerebrovascular accident; ESRD, end-stage renal disease; FDA, the Food and Drug Administration; GFR, glomerular filtration rate; HD, hemodialysis; MI, myocardial infarction; NSTEMI, non–ST-segment elevation myocardial infarction; UA, unstable angina.

    • Early dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 inhibitor is strongly recommended for patients with NSTEMI/UA without a contraindication (e.g., uncontrolled severe bleeding, recent neuraxial surgery or trauma, recent hemorrhagic stroke, or intra-cranial or spinal metastases).
    • DAPT should ideally be continued for 12 months from the index ACS event, regardless of whether revascularization is performed or not. See the 2016 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease for specific recommendations tailored to stent type, bleeding risk, and other considerations.18
    • Aspirin blocks platelet aggregation within minutes.
      • A chewable 162–325-mg dose of ASA should be administered immediately at symptom onset or at first medical contact, unless a contraindication exists. This should be followed by ASA 81 mg daily indefinitely.
      • If an ASA allergy is present, clopidogrel may be substituted. An allergy consultation should be obtained for possible desensitization, preferably before the need for a coronary stent.
      • After PCI, ASA 81 mg is the current recommended dose in the setting of DAPT.
    • Clopidogrel is a prodrug whose metabolite blocks the P2Y12 receptor and inhibits platelet activation and aggregation by blocking the adenosine diphosphate receptor site on platelets.
      • The addition of clopidogrel to ASA reduced cardiovascular mortality and recurrent MI both acutely and at 11 months of follow-up.12
      • A loading dose of 600 mg should always be given in naïve patients.
      • In patients unable to take oral medications or unable to absorb oral medications because of ileus, rectal administration is unproven but has been reported. Alternatively, parenteral agents (e.g., cangrelor or eptifibatide), may be considered.
      • It can be used as part of the protocol in both the ischemia-driven and routinely invasive strategies.
    • Prasugrel is also a prodrug that blocks the P2Y12 adenosine receptor; its conversion to its active metabolite occurs faster and to a greater extent than clopidogrel.
      • It results in faster, greater, and more uniform platelet inhibition compared to clopidogrel at the expense of higher risk of bleeding.14
      • It decreases risk of CVD death, MI, CVA, and acute stent thrombosis as compared to clopidogrel in ACS patients, including STEMI patients.
      • It should be used with caution or avoided in patients older than 75 years and who weigh less than 60 kg. It is contraindicated in those with prior stroke or transient ischemic attack.
      • It is used only in the invasive approach of ACS and only after coronary anatomy is known and PCI is planned. There is no benefit over clopidogrel when tested before the initiation of PCI.
    • Ticagrelor is not a prodrug and blocks the P2Y12 adenosine receptor directly.
      • It reduces the risk of death, MI, CVA, and stent thrombosis as compared to clopidogrel in ACS patients, including STEMI patients.13
      • After the loading dose of ASA, the maintenance dose of ASA must be <100 mg.
      • It can be used as part of the protocol in both the ischemia-driven and early invasive strategies.
      • Barring any contraindication, ticagrelor is the preferred P2Y12 inhibitor of choice because of the mortality advantage over medications in this class.
      • The relative contraindications include baseline bradycardia, severe reactive airways disease, and prior hemorrhagic stroke.
    • Cangrelor is a parenteral, direct, and reversible inhibitor of the P2Y12 adenosine receptor.
      • It has a uniquely rapid onset (<2 minutes), potency (>90% platelet inhibition), and short duration of action after cessation (normal platelet function after 1 hour).
      • It reduces the risk of death, MI, urgent revascularization, or stent thrombosis among patients undergoing PCI.19
      • The FDA approved it only for patients undergoing PCI and is currently very expensive. Thus, it is not yet recommended for routine use in either ischemia-guided or invasive strategy. Thus, we recommend consulting a cardiologist before the use of cangrelor.
      • It is sometimes used as a bridging strategy in patients who have had recent PCI and require surgery where DAPT is prohibited. This approach is of unproven benefit.
    • Glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists (abciximab, eptifibatide, or tirofiban) block the interaction between platelets and fibrinogen, thus targeting the final common pathway for platelet aggregation.
      • GPIIb/IIIa inhibitors play a limited role in ACS management with the introduction of more potent oral antiplatelet agents.
      • The routine use of GPIIb/IIIa antagonists on initial presentation, before angiography, in patients undergoing the invasive approach should be avoided because of increased risk of major bleeding and a lack of improvement in outcomes.
      • GPIIb/IIIa agents may be considered in scenarios of worsening ischemia despite DAPT, complex PCI, or bridging strategy in patients with an indication for DAPT (e.g., recent PCI) but require surgery.
      • Thrombocytopenia, which can be severe, is an uncommon complication of these agents and should prompt discontinuation.
    • Other concerns with antiplatelet agents
      • Timing of CABG
        • Owing to the increased risk of bleeding, it is currently recommended that clopidogrel be withheld for at least 5 days before CABG, prasugrel 7 days prior, ticagrelor 5 days prior, and cangrelor 1–6 hours prior.
        • Cangrelor or GPIIb/IIIa antagonists can be used as an alternative to clopidogrel, ticagrelor, and prasugrel in appropriate patients with UA/NSTEMI who are known to require surgical revascularization.
        • In general, DAPT should not be withheld during the initial management of ACS (i.e., before angiography) out of concern for the potential need for surgical revascularization. There is a larger risk of withholding beneficial therapy to patients in this setting than causing harm by delaying surgical revascularization.
      • Proton pump inhibitors (PPIs)
        • PPIs should be used in patients on DAPT with a prior history of gastrointestinal bleeding or increased risk of bleeding (e.g., elderly, known ulcers or Helicobacter pylori infection, or coprescribed warfarin, steroids, or NSAIDs).20
        • Pharmacologic studies have raised concerns about the potential of PPIs to blunt the efficacy of clopidogrel. However, in a prospective randomized trial, no apparent cardiovascular interaction was noted between PPIs and clopidogrel.19
      • Triple Therapy
        • Many patients requiring DAPT after PCI have a pre-existing indication for oral anticoagulation (OAC), such as atrial fibrillation or recent venous thromboembolism.
        • The use of DAPT and OAC (triple therapy) leads to higher bleeding risk, but recent trials suggest that triple therapy may not significantly reduce ischemic events any more than single antiplatelet therapy (SAPT; e.g., aspirin or clopidogrel) plus OAC.21,22
        • The most recent guidelines have not yet made specific recommendations, but they generally support tailoring selection of triple therapy (DAPT plus OAC) or SAPT plus OAC to the patient by comparing the risk of bleeding to the risk of ischemic events.18
        • In patients with an average risk of bleeding and average risk of ischemic events, we recommend triple therapy (e.g., aspirin, clopidogrel, and warfarin) for 4 weeks followed by SAPT plus OAC (e.g., clopidogrel and warfarin) for at least 1 year.
        • In patients with either high risk of bleeding or high risk of ischemic events, we recommend consultation with a cardiologist to tailor therapy.
  • Anticoagulant therapy
    • See Table 4-14 for recommended use and dosing in ACS.
      Table 4-14: Anticoagulant Medications
      MedicationDosageComments
      Heparin (UFH)60 units/kg IV bolus (maximum dose: 4000 units), 12–14 units/kg per hourHeparin therapy, when used in conjunction with ASA, has been shown to reduce the early rate of death or MI by up to 60%.23
      The aPTT should be adjusted to maintain a value of 1.5–2.0 times control.
      Enoxaparin (LMWH)1 mg/kg SC bidaLMWH is at least as efficacious as UFH and may further reduce the rate of death, MI, or recurrent angina.24
      LMWH may increase the rate of bleeding and cannot be reversed in the setting of refractory bleeding.25
      LMWH does not require monitoring for clinical effect.
      Fondaparinux2.5 mg SC dailyFondaparinux has efficacy similar to that of LMWH with possibly reduced bleeding rates.26
      Bivalirudinb0.75 mg/kg IV bolus, 1.75 mg/kg per hourWhen used in conjunction with ASA and clopidogrel, bivalirudin is at least as effective as the combination of ASA, UFH, clopidogrel, and GPIIb/IIIa antagonists with decreased bleeding rates.27 May increase risk for stent thrombosis.
      Monitoring is required with a goal aPTT of 1.5–2.5 times control.

      aLMWH should be given at reduced dose (50%) in patients with a serum creatinine >2 mg/dL or GFR <30 mL/min.

      bBivalirudin requires dosage adjustment in patients with a GFR less than 30 mL/min or those on hemodialysis.

      aPTT, activated partial thromboplastin time; ASA, aspirin; GFR, glomerular filtration rate; GP, glycoprotein; LMWH, low–molecular-weight heparin; MI, myocardial infarction; UFH, unfractionated heparin.

    • Anticoagulation accompanied by DAPT is required for all UA/NSTEMI patients, whether along the early invasive or conservative pathway.
    • Unfractionated heparin (UFH) works by binding antithrombin III, which catalyzes the inactivation of thrombin and other clotting factors.
      • Most commonly used and easily monitored but also most inconsistent in its anticoagulation and metabolism.
      • Heparin-induced thrombocytopenia (HIT) is a concern with prior use.
      • Easily reversed in the event of a severe hemorrhagic complication.
      • Always requires aggressive bolus dosing and anticoagulation monitoring in the setting of ACS.
      • Is a recommended anticoagulant to be used in the setting of ACS.
    • Low–molecular-weight heparin (LMWH) inhibits mostly factor Xa but also affects thrombin activity and offers an ease of administration (weight-based, twice-daily subcutaneous dose). The risk of HIT is lower but not absent.
      • As compared to UFH, LMWH has a more predictable anticoagulant effect.
      • It has a similar efficacy as UFH but is associated with a higher risk of postprocedural bleeding.25
      • LMWH must be adjusted for renal dysfunction and should be avoided in patients with severe impairments.
      • Enoxaparin 0.3 mg/kg IV should be administered at the time of PCI in patients who have received less than two therapeutic doses or if the last dose was received more than 8 hours before PCI.
    • Fondaparinux is a synthetic polysaccharide that selectively inhibits factor Xa and can be subcutaneously administered on a daily routine.
      • It is associated with an increased risk of thrombosis during PCI and should not be used without additional antithrombin anticoagulation; as such, it is not recommended for the routine management of ACS.
      • In patients not undergoing invasive management, fondaparinux may significantly reduce bleeding and improve outcomes compared to LMWH.28
    • Bivalirudin is a direct thrombin inhibitor given as a continuous IV infusion and requires partial thromboplastin time (PTT) monitoring when used for >4 hours.
      • It does not cause HIT and is used in the treatment of patients who develop HIT or patients with ACS who have history of HIT.
      • Bivalirudin can be given in conjunction with ASA and clopidogrel in patients presenting with UA/NSTEMI who will undergo a routine invasive strategy.
      • Bivalirudin alone compared to UFH/LMWH + GPIIb/IIIa inhibitor was associated with less bleeding.27
      • Recent evidence has shown that in ACS without significant GPIIb/IIIa inhibitor use, bivalirudin is associated with increased risk of stent thrombosis and target lesion revascularization.29
      • Caution should be taken with routine use of bivalirudin in ACS unless there is a high risk of bleeding.
  • Anti-ischemic therapy (please also refer to Treatment section of stable angina)
    • Nitroglycerin
      • Treatment can be initiated at the time of presentation with sublingual nitroglycerin. NOTE: 40% of patients with chest pain not due to CAD will get relief with nitroglycerin (see Table 4-10).30
      • Patients with ongoing ischemic symptoms or those who require additional agents to control significant hypertension can be treated with IV nitroglycerin until pain relief, hypertension control, or both are achieved.
      • Rule out right ventricular (RV) infarct before administration of nitrates because this can precipitate profound hypotension.
    • β-Adrenergic blockers (BBs) (please also refer to the Treatment section for stable angina)
      • Oral therapy should be started early in the absence of contraindications.
      • Treatment with an IV preparation should be reserved for treatment of arrhythmia, ongoing chest pain, or advanced hypertension rather than routine use.
      • Routine use of IV BBs is associated with increased risk of cardiogenic shock and should be avoided.
      • Contraindications to BB therapy include advanced AV block, active bronchospasm, decompensated HF, cardiogenic shock, hypotension, and bradycardia.
    • Morphine 2–4 mg IV may be used as an adjunct to BB, nitrates, and calcium channel blockers. Care must be taken on not to mask further clinical evaluation by heavy use of narcotic medications.
  • Adjunctive medical therapy
    • ACE inhibitors (refer to Treatment section for stable angina) are effective antihypertensive agents and have been shown to reduce mortality in patients with CAD and LV systolic dysfunction. ACE inhibitors should be used in patients with LV dysfunction (EF <40%), hypertension, or diabetes presenting with ACS. ARBs are appropriate in patients who cannot tolerate ACEIs.
    • Aldosterone antagonists should be added, if there are no contraindications (potassium >5 mEq/L or creatinine clearance [CrCl] <30 mL/min), after initiation of ACE inhibitors in patients with diabetes or an LVEF <40%.
    • 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors (statins) are potent lipid-lowering agents that reduce the incidence of ischemia, MI, and death in patients with CAD. High-intensity statins should be routinely administered within 24 hours of presentation in patients presenting with ACS. A lipid profile should be obtained in all patients.
      • Statin therapy reduces adverse outcomes through lipid lowering and potentially through pleiotropic effects (anti-inflammatory/atherosclerotic plaque–stabilizing effects).
      • Aggressive statin therapy reduces the risk of recurrent ischemia, MI, and death in patients presenting with ACS.31
      • A reduction in adverse CVD outcomes following early initiation of a high-dose statin with achievement of an LDL <70 mg/dL can be seen as early as 30 days following initial presentation with ACS.32 Aggressive LDL lowering also reduces the incidence of periprocedural MI following PCI.33
      • Patients who cannot achieve LDL <70 mg/dL after the use of a high-intensity statin should be evaluated for adjunctive PCSK9 inhibitors or ezetimibe.34,35 (Please refer to “Treatment” section for stable angina)
    • NSAIDs are associated with an increased risk of death, MI, myocardial rupture, hypertension, and HF in large meta-analyses.36 Adverse outcomes have been observed for both nonselective and cyclooxygenase-2 (COX-2) selective agents. NSAIDs should be discontinued in patients presenting with UA/NSTEMI.
    • Blood glucose should not be tightly controlled in diabetic patients who have suffered ACS because it may increase mortality. Goal is <180 mg/dL while avoiding hypoglycemia at all costs.

Revascularization

  • PCI
    • Please see “Revascularization” section under Stable Angina for invasive management strategies.
  • CABG
    • The indications for PCI versus CABG in patients with UA/NSTEMI are similar to those for individuals with chronic stable angina (please see section on “Revascularization” under Stable Angina).
    • The urgency of revascularization should weigh heavily in the decision for CABG; patients in cardiogenic shock may benefit from PCI and mechanical support compared to emergency cardiac surgery.
    • NSTEMI in the setting of critical left main CAD should prompt urgent surgical revascularization and consideration of intra-aortic balloon pump (IABP) for stabilization before the induction of anesthesia.

Monitoring/Follow-Up

The highest rate of progression to MI or development of recurrent MI is in the first 2 months after presentation with the index episode. Beyond that time, most patients have a clinical course similar to those with chronic stable angina.

  • Patients should be discharged on dual antiplatelet, BB, and statin therapy.
  • Most patients should be discharged on ACE inhibitors.
  • Patients should be evaluated for the need of aldosterone antagonists.
  • Screening for life stressors and depression should be carried out. Refer for depression treatment as needed.
  • Smoking cessation and risk factor modification should be stressed.
  • Referral to cardiac rehabilitation should also be pursued.

References

  1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes. J Am Coll Cardiol. 2014;64(24):e139-228.  [PMID:25260718]
  2. Stone PH, Thompson B, Anderson HV, et al. Influence of race, sex, and age on management of unstable angina and non—Q-wave myocardial infarction: the TIMI III registry. JAMA. 1996;275(14):1104-1112.  [PMID:8601930]
  3. Killip T, Kimball JT. Treatment of myocardial infarction in a coronary care unit. A two year experience with 250 patients. Am J Cardiol. 1967;20(4):457-464.  [PMID:6059183]
  4. de Zwaan C, Bär FW, Wellens HJ. Characteristic electrocardiographic pattern indicating a critical stenosis high in left anterior descending coronary artery in patients admitted because of impending myocardial infarction. Am Heart J. 1982;103(4 pt 2):730-736.  [PMID:6121481]
  5. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. GUSTO IIA investigators. N Engl J Med. 1996;335(18):1333-1341.  [PMID:8857016]
  6. Newby LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. Circulation. 1998;98(18):1853-1859.  [PMID:9799204]
  7. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002;105(15):1760-1763.  [PMID:11956114]
  8. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk Score for unstable angina/non–ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284(7):835-842.  [PMID:10938172]
  9. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non–ST-elevation myocardial Infarction: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (writing committee to revise the 2002 guidelines for the management of Patients with unstable angina/non–ST-elevation myocardial infarction): developed in collaboration with the American College of emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007;116(7):e148-e304.  [PMID:17679616]
  10. Hofmann R, James SK, Jernberg T, et al. Oxygen therapy in suspected acute myocardial infarction. N Engl J Med. 2017;377(13):1240-1249.  [PMID:28844200]
  11. Wijesinghe M, Perrin K, Ranchord A, et al. Routine use of oxygen in the treatment of myocardial infarction: systematic review. Heart Br Card Soc. 2009;95(3):198-202.
  12. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345(7):494-502.
  13. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.  [PMID:19717846]
  14. Wiviott SD, Trenk D, Frelinger AL, et al. Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention: the Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 44 trial. Circulation. 2007;116(25):2923-2932.  [PMID:18056526]
  15. Kleiman NS, Lincoff AM, Flaker GC, et al. Early percutaneous coronary intervention, platelet inhibition with eptifibatide, and clinical outcomes in patients with acute coronary syndromes. Circulation. 2000;101(7):751-757.  [PMID:10683348]
  16. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med. 1998;339(7):436-443.
  17. Batchelor WB, Tolleson TR, Huang Y, et al. Randomized comparison of platelet inhibition with abciximab, tirofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes. Circulation. 2002;106:1470-1476.  [PMID:12234950]
  18. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines: an update of the 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention, 2011 ACCF/AHA guideline for coronary artery bypass graft surgery, 2012 ACC/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease, 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction, 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes, and 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery. Circulation. 2016;134(10):e123-e155.  [PMID:27026020]
  19. Bhatt DL, Stone GW, Mahaffey KW, et al. Effect of platelet inhibition with cangrelor during PCI on ischemic events. N Engl J Med. 2013;368(14):1303-1313.  [PMID:23473369]
  20. Members WC, Abraham NS, Hlatky MA, et al. ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology foundation task force on expert consensus documents. Circulation. 2010;122(24):2619-2633.
  21. Gibson CM, Mehran R, Bode C, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med. 2016;375(25):2423-2434.  [PMID:27959713]
  22. Dewilde WJM, Oirbans T, Verheugt FWA, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115.
  23. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA. 1996;276(10):811-815.  [PMID:8769591]
  24. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337(7):447-452.  [PMID:9250846]
  25. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292(1):45-54.  [PMID:15238590]
  26. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354(14):1464-1476.  [PMID:16537663]
  27. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355(21):2203-2216.  [PMID:17124018]
  28. Szummer K, Oldgren J, Lindhagen L, et al. Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction. JAMA. 2015;313(7):707-716.  [PMID:25688782]
  29. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384(9957):1849-1858.  [PMID:25002178]
  30. Henrikson CA, Howell EE, Bush DE, et al. Chest pain relief by nitroglycerin does not predict active coronary artery disease. Ann Intern Med. 2003;139(12):979-986.  [PMID:14678917]
  31. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711-1718.  [PMID:11277825]
  32. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495-1504.  [PMID:15007110]
  33. Patti G, Pasceri V, Colonna G, et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol. 2007;49(12):1272-1278.  [PMID:17394957]
  34. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722.  [PMID:28304224]
  35. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387-2397.  [PMID:26039521]
  36. Gislason GH, Jacobsen S, Rasmussen JN, et al. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation. 2006;113(25):2906-2913.  [PMID:16785336]

Outline


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