Description

• Unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI) are acute coronary syndromes without ST-segment elevation (NSTE-ACS) that are differentiated from one another based on the myocardial necrosis/damage (no elevation in cardiac biomarkers in UA) that is present in NSTEMI.
• UA and NSTEMI are difficult to distinguish initially because elevation in troponin levels may not be detectable until several hours after presentation. Initial management for both syndromes is similar.
• Patient history alone is not sufficient to make a diagnosis of ACS, and the clinical dilemma of distinguishing between cardiac and noncardiac chest pain involves a combination of patient history, ECG, and cardiac biomarkers.

Epidemiology

Incidence

• The estimated annual incidence of new and recurrent MI is 605,000 and 200,000, respectively.
• In the United States, the average age at first MI is 65.6 years for males and 72.0 years for females, and males outnumber females at a 3:2 ratio.

Etiology and Pathophysiology

• NSTE-ACS is due to a sudden decrease in myocardial blood flow, resulting in an imbalance between myocardial oxygen consumption and demand. This can be due to acute plaque rupture or plaque erosion and leads to a partially occluding thrombus in the coronary artery, rather than a total or complete occlusion as seen in STEMI.
• Other mechanisms of NSTE-ACS include:
  • Prinzmetal angina or coronary vasospasm induced by tobacco use, hyperventilation, magnesium deficiency, cocaine, or methamphetamines.
  • Increased myocardial oxygen demand resulting in supply-demand mismatch (type 2 NSTEMI) due to underlying causes such as pulmonary embolism, sepsis, shock, and arrhythmias/tachycardia
  • Coronary microvascular dysfunction or endothelial dysfunction without epicardial coronary obstruction
  • Less commonly: coronary arterial aneurysm, spontaneous coronary artery dissection, and thromboembolism

Genetics
Genetic polymorphisms of MMP-3 5A/6A and ACE I/D along with conventional ischemic heart disease risk factors can increase the risk of occurrence of STEMI, while having no influence on the pathogenesis of NSTEMI or UA.

Risk Factors

• Traditional/classic: age, male sex, prior MI, hypertension (HTN), tobacco use, diabetes mellitus (DM), dyslipidemia, and family history of premature CAD (defined as age of onset prior to 55 years in males and 65 years in females)
• Novel/emerging risk factors: sedentary lifestyle, overweight/obesity (metabolic syndrome), inflammation (psoriasis, rheumatoid arthritis), cigarette smoking, psychosocial factors (anxiety/depression/stress), chronic kidney disease (CKD), obstructive sleep apnea, environmental pollutants

General Prevention

Smoking cessation, normal body mass index, stress management, regular physical activity, glycemic control for patients with diabetes and blood pressure (BP) control in patients with HTN, risk-based statins, aspirin in those with documented CAD

History

• Chest heaviness/tightness lasting ≥10 minutes; with or without exertion; typically retrosternal and can radiate to the neck, jaw, interscapular area, upper extremities, or epigastrium; pain is typically described as a pressure, tightness, heaviness, squeezing, or fullness.
• Associated symptoms of palpitations, dyspnea, nausea/vomiting, diaphoresis, light-headedness, syncope, or dysphoria can occur.
• Atypical symptoms: stabbing or pleuritic pain, epigastric/abdominal pain, indigestion or isolated dyspnea; more common in those aged >75 years, in women, or in those with diabetes, renal insufficiency, and dementia; may present without chest pain and with symptoms of dyspnea, diaphoresis, and extreme fatigue which represent “anginal equivalents”

Physical Exam

• Tachycardia or bradycardia, HTN or hypotension, widened pulse pressure, tachypnea, fever, poor dental hygiene
• Dysrhythmia, jugular venous distention (JVD), new murmur (third and fourth heart sounds), rub or gallop, diminished peripheral pulses, carotid bruits
• Tachypnea, ↑ work of breathing, crackles
• Pain reproducible with movement or palpation is unlikely to be cardiac.
• Cool skin, pallor, diaphoresis, signs of dyslipidemia (xanthomas, xanthelasma)

Differential Diagnosis

• Cardiac: aortic dissection, myocarditis, pericarditis, pericardial effusion/cardiac tamponade, heart failure with preserved and reduced ejection fraction, hypertensive emergency, stress cardiomyopathy (takotsubo), dysrhythmia, and mitral valve disease
• Pulmonary: pulmonary embolism, pneumothorax, pneumonia, pleuritis, bronchitis, pneumonitis, and pleuritis
• Psychiatric: panic attacks, anxiety
• Musculoskeletal: costochondritis, rib fracture
• Gastroenterology: gastroesophageal reflux disease, esophageal spasm, esophagitis, esophageal rupture or perforation, hiatal hernia, penetrating or perforating peptic ulcer, biliary or pancreatic pain

Diagnostic Tests & Interpretation

Initial Tests (lab, imaging)

• 12-lead ECG: should be obtained within 10 minutes of presentation; applies to both UA and NSTEMI
• CBC, BMP (to evaluate for electrolyte abnormalities), and serum troponin biomarkers (negative by definition in UA), which can be elevated within the first 2 to 3 hours since the onset of chest pain
• Chest x-ray, computed tomography with contrast (to exclude other etiologies if applicable), and transthoracic echocardiography are recommended.

Follow-Up Tests & Special Considerations
Fasting lipid profile, preferably within 24 hours, activated partial thromboplastin time (aPTT), TSH, HbA1c, and urine drug screen (in selected patients)

Diagnostic Procedures/Other

• For low- to intermediate-risk patients with resolution of symptoms and nondiagnostic ECG with negative biomarkers, consider noninvasive cardiac testing with standard exercise treadmill test, exercise stress echocardiography, or myocardial perfusion imaging using single-photon emission computed tomography.
• Alternatively, coronary computed tomography angiography can be performed as well in the same population at low to intermediate risk.

Test Interpretation

• ECG results in the setting of NSTE-ACS:
  • New ST-segment depression ≥0.5 mm in two or more contiguous leads and/or T-wave inversions ≥1 mm in two or more contiguous leads
  • ST depression and/or tall R wave in V₁/V₂ with upright T waves may indicate transmural STEMI of posterior wall. ECG with posterior leads (V₇V₉) should be performed.
  • If initial ECG is nondiagnostic but symptoms persist with suspicion for ACS, perform serial ECGs at 15- to 30-minute intervals.
• Troponin concentration rises within 3 to 6 hours after onset of ischemic symptoms but can be delayed up to 8 to 12 hours (troponin T is not specific in patients with renal dysfunction).
  • NSTEMI can be diagnosed by initial concentration of >52 ng/L or a change in level from initial reading after 2 hours >10 ng/L.
  • In patients with symptoms suggestive of ACS, negative troponin at 6 hours can almost effectively rule out infarct in most patients (1).
  • CK-MB has been shown to have better specificity than troponin in post-PCI MI. Troponin elevation will resolve in 3 to 10 days, CK-MB will return to normal within 3 to 4 days (1).
  • Repeat biomarkers 8 to 12 hours from onset of symptoms to check if troponin levels have peaked. The expected rise and fall of troponin level in the setting of MI is an important diagnostic factor that can distinguish an MI from alternative causes of elevated troponin (1).

General Measures

• Initial ABCDs; assess clinical stability (adequate oxygenation) and determine the next step.
• Risk stratify (TIMI or GRACE score) to select invasive approach (coronary angiography within 24 hours of admission) versus ischemia-guided therapy; urgent invasive management is required for very high-risk patients, such as those with hemodynamic instability, cardiogenic shock, recurrent or ongoing chest pain refractory to medical therapy, or life-threatening arrhythmias or cardiac arrest.
• TIMI risk score includes age >65 years, ≥3 CAD risk factors, known CAD with >50% stenosis, aspirin use within the last 7 days, severe angina in the preceding 24 hours, elevated cardiac markers, and ST deviation >0.5 mm. Low risk is a score of 0 to 2, intermediate risk with a score of 3 to 4, and high risk with a score of 5 to 7.
• GRACE risk score calculation uses eight parameters to predict death and MI in the hospital and at 6 months, which include age, heart rate, systolic BP, creatinine, Killip classification for heart failure, cardiac arrest, ST-segment deviation, and elevated cardiac enzymes.
• Bed/chair rest with continuous ECG monitoring, maintaining O₂ saturation >90%, and tight BP control; discontinue NSAIDs if possible. Support smoking cessation. Correct electrolyte abnormalities with potassium goal around 4 mEq/L and magnesium at 2 mg/dL.

Medication

First Line

• Antiplatelet therapy: dual antiplatelet therapy for all patients with NSTE-ACS
• Aspirin, nonenteric coated, initial dose of 162 to 325 mg chewed or crushed; maintenance dose of 75 to 100 mg/day indefinitely, which can reduce the risk of death, MI, and stroke
• P2Y12 inhibitors should be given at the time of diagnosis unless invasive approach is planned in a high-bleeding risk patient:
  • Ticagrelor, loading dose of 180 mg PO, followed by 90 mg PO twice daily; avoid in patients with 2nd- and 3rd-degree heart block; can cause dyspnea in some patients; contraindicated in patients with severe liver dysfunction or
  • Prasugrel 60 mg PO, followed by maintenance dose of 10 mg PO daily; often reserved for post-PCI patients treated with coronary stents; contraindicated in patients aged ≥75 years or those with history of CVA/TIA or
  • Clopidogrel, loading dose of 300 to 600 mg PO, followed by maintenance dose of 75 mg PO daily; use with caution with thrombocytopenia and CKD (adding clopidogrel to aspirin may reduce the combined outcome of mortality).
• Nitroglycerin sublingual 0.4 mg every 5 minutes for total of 3 doses and then assess need for IV nitroglycerin based on blood pressure and pain relief. Nitroglycerin-induced hypotension may be attenuated with right ventricular infarction.
• Morphine sulfate (initial dose of 2 to 4 mg), with increments of 2 to 8 mg, can be repeated at 5- to 15-minute intervals for relief of severe, persistent chest pain.
• Oral β-blocker therapy should be initiated within 24 hours in patients without signs of heart failure, cardiogenic shock, or other contraindications to β-blockade (2nd- or 3rd-degree heart block without a pacemaker or active asthma).
  • In patients with concomitant ACS, stabilized heart failure, and reduced systolic function (LVEF <40%), the recommended β-blockers are metoprolol succinate, carvedilol, and bisoprolol.
• Lipid-lowering therapy: Initiate or continue high-intensity statin therapy (preferred due to nonlipid benefit on vascular function) with atorvastatin 80 mg/day or rosuvastatin 20 to 40 mg/day regardless of the patient’s baseline LDL level. Ezetimibe and PCSK9 inhibitors (evolocumab, alirocumab) can be considered in statin-intolerant patients/complementary therapy.
• ACE inhibitor (ACEi) should be started and continued indefinitely in all patients with LVEF <40% and in those with diabetes or HTN, and it can lead to improved 30-day mortality in patients after an acute STEMI.
• Aldosterone antagonist (spironolactone or eplerenone) is recommended in NSTEMI for patients without significant renal dysfunction or hyperkalemia who are on a therapeutic dose of ACEi/ARB and β-blocker and have LVEF ≤40%, DM, or heart failure.
• Antithrombotic therapy: Initiate anticoagulant (unfractionated heparin, enoxaparin, bivalirudin or fondaparinux) therapy as soon as possible after presentation. For patients undergoing invasive management (PCI), stop at the end of procedure. For patients being treated with conservative approach, continue for a minimum of 48 hours. Unfractionated or low-molecular-weight heparin plus aspirin may reduce death or MI at 1 week, but longer-term benefits are unclear at this time. Warfarin has not been shown to be beneficial and can increase the risk of major bleeding.

Second Line
Nondihydropyridine calcium channel blockers (CCB) (verapamil or diltiazem) are used to reduce myocardial oxygen demand when β-blockers are contraindicated if left ventricular ejection fraction is normal. Long-acting CCBs are recommended in treatment of patients with epicardial or microvascular coronary artery spasm. Avoid in patients with heart block.

Issues For Referral

• Cardiology consultation is indicated for NSTE-ACS.
• Referral to exercise-based cardiac rehabilitation program prior to hospital discharge is associated with decreased morbidity and mortality.

Surgery/Other Procedures

Some patients often undergo exercise stress testing a few weeks or more after hospital discharge as part of a cardiac rehabilitation program for activity counseling.

Follow-up Recommendations

• Patients with low-risk suspected ACS who have normal serial ECGs and cardiac troponin levels may have a treadmill ECG, stress myocardial perfusion imaging, or stress echocardiography within 72 hours after discharge.
• With LVEF <40%, repeat LVEF 1 to 3 months postdischarge.

Diet

• 1/3 of deaths caused by cardiovascular disease (CVD) can be prevented through healthy lifestyle choices including diet and physical activity.
• The Mediterranean diet is associated with reduced CVD mortality, whereas DASH diet is associated with reduced risk of CAD.
• There is an association with increased sodium intake and CVD risk, but reducing dietary sodium has not been shown to reduce CVD risk.

Patient Education

• May resume exercise and sexual activity within 2 weeks in asymptomatic patients after outpatient reevaluation
• Exercise recommendations for adults include at least 150 minutes of moderate-intensity aerobic activity per week and are associated with reduced CVD risk.

Prognosis

• 50% of patients with UA progress to myocardial infarction within 30 days if left untreated.
• Between 9% and 19% of those with ACS die in the first 6 months after initial diagnosis, with about 1/2 of these deaths occurring within the first 30 days.

ICD-10

• I20.0 Unstable angina
• I21.4 Non-ST elevation (NSTEMI) myocardial infarction
• I24.9 Acute ischemic heart disease, unspecified

SNOMED

• 394659003 Acute coronary syndrome (disorder)
• 401314000 Acute non-ST segment elevation myocardial infarction (disorder)
• 4557003 Preinfarction syndrome (disorder)