Acute Coronary Syndromes, Unstable Angina

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.²⁹^,³⁰

Epidemiology

The annual incidence of 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.³¹^,³²
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.

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.
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 use), coronary artery dissection (more common in women), coronary vasculitis, and embolus.

Clinical Presentation

History

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 mitral regurgitation [MR] murmur), elevated jugular venous pulsation, pulmonary edema, hypotension, and peripheral edema worsen the prognosis.
Killip classification can be useful to risk stratify and identify patients with features of cardiogenic shock (Table 4-10 - Killip Classification³³).
Examination may also give clues to other causes of ischemia such as thyrotoxicosis or aortic dissection (see Table 4-4 - Conditions That May Provoke or Exacerbate Ischemia/Angina Independent of Worsening Atherosclerosis).

Diagnostic Testing

Electrocardiography

Prior to 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 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.³²^,³⁴
- ST-segment depression in two contiguous leads is a sensitive indicator of myocardial ischemia, especially if dynamic and associated with symptoms.
  - 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).³⁴
- Nonspecific ST-segment changes or T-wave inversions (those that do not meet voltage criteria) are nondiagnostic and unhelpful in 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).
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 magnitude of increase in troponin.³⁴
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.³⁵ Severe elevations of BNP in the setting of ACS in patients without known HF should raise concern for a large infarction and urgent angiography.

Acute treatment aims to reduce the symptoms of chest pain and risk 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 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).
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 4-11 - Appropriate Selection of Routine Invasive Versus Ischemia-Driven Revascularization Strategy in Patients With NSTEMI/UA summarizes the selection approach.
- 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 prior to 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 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 4-11 - Appropriate Selection of Routine Invasive Versus Ischemia-Driven Revascularization Strategy in Patients With NSTEMI/UA).
  - Note: 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 chronic kidney disease, 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 (<SpO₂ 90%) or having difficulty breathing. Routine use of oxygen is not needed and possibly harmful.³⁸
Antiplatelet therapy
- Table 4-12 - Antiplatelet Agents in UA/NSTEMI summarizes available agents and dosing recommendations for use in ACS.
- 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 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.
- Aspirin blocks platelet aggregation within minutes.
  - A chewable 162- to 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 a substitution. An allergy consultation should be obtained for possible desensitization, preferably prior to 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.³⁹
  - 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 due to ileus, rectal administration is unproven but has been reported. Alternatively, parenteral agents (e.g., cangrelor or eptifibatide) may be considered.
  - 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.
  - Results in faster, greater, and more uniform platelet inhibition compared to clopidogrel at the expense of higher risk of bleeding.⁵⁵
  - 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 (TIA).
  - 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 initiation of PCI.
  - Prasugrel may be superior to ticagrelor with regards to the composite of MI, stroke, and death.⁵⁶
- Ticagrelor is not a prodrug and blocks the P2Y₁₂ adenosine receptor directly.
  - Reduces the risk of death, MI, CVA, and stent thrombosis as compared to clopidogrel in ACS patients, including STEMI patients.⁴²
  - After the loading dose of ASA, the maintenance dose of ASA must be <100 mg.
  - 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 due to the mortality advantage over other medications in this class.⁴³
  - 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).
  - Reduces the risk of death, MI, urgent revascularization, or stent thrombosis among patients undergoing PCI.⁵⁷
  - FDA approved only for patients undergoing PCI, and 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.
  - 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.
  - Routine use of GPIIb/IIIa antagonists on initial presentation, before angiography, in patients undergoing the invasive approach should be avoided due to 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
    - Due to increased risk of bleeding, it is currently recommended that clopidogrel be withheld for at least 5 days prior to 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., prior to 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).⁵⁸
    - 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.⁵⁹
  - Triple therapy
    - Many patients requiring DAPT after PCI have a preexisting indication for oral anticoagulation (OAC), such as atrial fibrillation or recent venous thromboembolism.
    - The most recent guidelines have not yet made specific recommendations, but generally support tailoring selection of triple therapy (DAPT plus OAC) or SAPT (single antiplatelet therapy) plus OAC to the patient by comparing the risk of bleeding to the risk of ischemic events.⁶⁰^,⁶¹^,⁶²
      - In the AUGUSTUS trial, patients with atrial fibrillation and recent ACS or PCI treated with a P2Y₁₂ inhibitor and apixaban, without aspirin, had fewer bleeding events and fewer hospitalizations without significantly increased ischemic events versus regimens including warfarin, aspirin, or both.⁶³
    - 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 4-13 - Anticoagulant Medications for recommended use and dosing in ACS.
- 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.
  - 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.⁶⁸
  - 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 X and can be subcutaneously administered on a daily routine.
  - 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.⁶⁹
- 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.⁷⁰
  - 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.⁷¹
  - Caution should be used 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 nitroglycerin⁶² (see Table 4-9 - Nitrate Preparations Commonly Used for Ischemic Heart Disease).
  - 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 prior to 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 used 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 ACE inhibitors.
- 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 to 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.
  - Aggressive statin therapy reduces the risk of recurrent ischemia, MI, and death in patients presenting with ACS.⁶²
  - 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.⁷² Aggressive LDL lowering also reduces the incidence of periprocedural MI following PCI.⁶⁷^,⁷³
- NSAIDs are associated with an increased risk of death, MI, myocardial rupture, hypertension, and HF in large meta-analyses.⁷⁴ Adverse outcomes have been observed for both nonselective and selective cyclooxygenase-2 (COX-2) 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 “Revascularization” section 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 prior to the induction of anesthesia.

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General Principles ⬇

Treatment ⬆ ⬇

Information ⬆