Acute Coronary Syndromes: NSTE-ACS (Unstable Angina and NSTEMI)



  • Unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI) are acute coronary syndromes without ST-segment elevation (NSTE-ACS).
  • NSTEMI is defined by the rise and fall of cardiac biomarkers (preferably troponin I or T) with at least one value above the 99th percentile upper reference limit and accompanied by one of the following: symptoms of ischemia, new ST-segment/T-wave changes (such as ST depression or T-wave inversions), development of pathologic Q waves on 12-lead ECG, or noninvasive imaging with evidence of myocardium at risk for ischemia or a new regional wall motion abnormality.
  • UA is defined by the presence of clinical symptoms of cardiac ischemia (new-onset anginal chest pain, change in typical anginal pattern, development of angina at rest, or change in typical anginal equivalent), without evidence of myocardial necrosis as evidenced by normal cardiac biomarkers of injury (troponin). ECG changes, such as ST-segment depression or T-wave inversions, may be present.


Estimated annual incidence of new and recurrent MI is 605,000 and 200,000, respectively. In United States, average age at first MI is 65.6 years for males and 72.0 years for females (1).

An estimated 16.5 million Americans ≥20 years have coronary artery disease (CAD). Mortality: CAD is the leading cause of death in adults in the United States with overall age-adjusted mortality of 98.8/100,000. Death rate is higher in men.

Etiology and Pathophysiology

  • NSTE-ACS primarily due to a sudden decrease in myocardial blood flow due to acute plaque rupture or plaque erosion leading to partially occluding thrombus
  • Other mechanisms include (i) Dynamic obstruction triggered by intense spasm of an epicardial coronary artery (prinzmetal angina or coronary vasospasm induced by tobacco use, hyperventilation, magnesium deficiency, cocaine, or methamphetamine); (ii) increased myocardial oxygen demand resulting in supply-demand mismatch (type 2 NSTEMI) due to underlying causes such as pulmonary embolism, sepsis, shock, arrhythmias/tachycardia; (iii) coronary microvascular dysfunction or endothelial dysfunction without epicardial coronary obstruction; and (iv) less common causes include coronary arterial aneurysm, spontaneous coronary artery dissection, thromboembolism.

CAD is generally a complex, polygenic disorder.

Risk Factors

  • Traditional/classic: age (strongest risk factor), 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), psychosocial factors (anxiety/depression), chronic kidney disease (CKD), obstructive sleep apnea, environmental pollutants

General Prevention

Smoking cessation, a diet low in saturated fat, maintaining a normal body mass index, regular physical activity combined with risk factor control: glycemic control for patient with diabetes and blood pressure (BP) control in patients with HTN, risk-based statins; aspirin in those with documented CAD

Commonly Associated Conditions

Vascular disease, chronic kidney disease



  • Chest heaviness/tightness lasting ≥10 minutes; occurs with or without exertion. Pain or discomfort is 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, diaphoresis, light-headedness, syncope, or dysphoria can occur.
  • Patients, especially elderly, diabetics, and women, can present without chest pain and with symptoms of dyspnea, diaphoresis, and extreme fatigue which represent “anginal equivalents.”
  • Risk factors for CAD; use of cocaine or amphetamines

Physical Exam

General: Note vital signs (especially tachycardia or bradycardia, HTN or hypotension), widened pulse pressure, tachypnea, fever, poor dental hygiene. Cardiovascular: dysrhythmia, jugular venous distention (JVD), new murmur, rub or gallop, diminished peripheral pulses, carotid bruits. Respiratory: tachypnea, ↑ work of breathing, crackles. Musculoskeletal: Sharp pain reproducible with movement or palpation is unlikely to be cardiac. Skin: 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
  • 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
    • 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 with prominent R wave or R/S ratio >1
    • 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.
  • Completed blood count and serum biomarkers (negative by definition in UA)
    • Troponin concentration rises 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).
    • Ultra-high sensitive troponins have a higher sensitivity than standard assays, but further validation is required.
    • CK-MB has been shown to have better specificity than troponins in post-PCI MI. Troponin elevation will resolve in 3 to 10 days; CK-MB will return to normal within 3 to 4 days.
    • Repeat biomarkers 8 to 12 hours from onset of symptoms.
  • Chest x-ray, computed tomography with contrast to exclude other etiologies if applicable. Transthoracic echocardiography is recommended.

Follow-Up Tests & Special Considerations

  • Fasting lipid profile, preferably within 24 hours. Activated partial thromboplastin time (aPTT); TSH, HgbA1c
  • 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.


General Measures

  • Risk stratify (TIMI or GRACE score) to select use of early invasive approach (coronary angiography within 24 hours of admission) versus ischemia-guided therapy; urgent invasive management for very high-risk patients, such as those with hemodynamic instability or cardiogenic shock, recurrent or ongoing chest pain refractory to medical therapy, life-threatening arrhythmias or cardiac arrest, mechanical complications, acute heart failure, and recurrent dynamic ST-T wave changes
  • Bed/chair rest with continuous ECG monitoring, maintain O2 saturation >90%, and tight BP control. Discontinue NSAIDs if possible. Support smoking cessation. Correct electrolyte abnormalities (K+ and Mg++).


First Line

  • Antiplatelet therapy: Dual antiplatelet therapy is recommended for all patients with NSTE-ACS.
  • Aspirin, nonenteric coated, initial dose of 162 to 325 mg chewed or crushed for all patients; decreases mortality and morbidity; maintenance dose of 75 to 100 mg/day indefinitely
  • P2Y12 inhibitors:
    • Should be given at the time of diagnosis unless invasive approach is planned in a very high bleeding-risk patient
    • Ticagrelor, loading dose 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. PB2452, a monoclonal antibody fragment that binds ticagrelor, can be used as a reversal agent OR
    • Prasugrel 60 mg PO, followed by 10 mg PO daily. Often reserved for post-PCI patients treated with coronary stents; contraindicated in patients ≥75 years or those with history of CVA/TIA OR
    • Clopidogrel, loading dose 300 to 600 mg PO, followed by 75 mg PO daily. Use with caution in patients with thrombocytopenia and CKD. An estimated 15% of the general population clopidogrel “nonresponders.” Resistance can be tested with P2Y12 assay, although routine screening is not currently recommended (1).
    • Patients unable to take aspirin should receive loading and maintenance dose of a P2Y12 inhibitor.
    • GP IIb/IIIa inhibitors: Add eptifibatide or tirofiban in select high-risk patients (persistent chest pain, large thrombus burden on angiography) after PCI.
  • Supplemental oxygen may be given if oxygen saturations are <90% or in patients with heart failure symptoms.
  • Nitroglycerin sublingual 0.4 mg every 5 minutes for total of 3 doses and then assess need for IV nitroglycerin. Avoid if hypotension or if used phosphodiesterase inhibitors within the past 24 to 48 hours. Nitroglycerin-induced hypotension may be attenuated with right ventricular infarction.
  • Morphine sulfate 1 to 5 mg IV in patients with continuous ischemic chest pain, with increments of 2 to 8 mg repeated at 5- to 30-minute intervals
  • 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, active asthma). Recommended dose is metoprolol tartrate 25 to 50 mg every 6 to 12 hours. IV therapy may be considered in patients with severe ischemia.
  • 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 daily or rosuvastatin 20 to 40 mg daily regardless of the patient’s baseline LDL level. Ezetimibe, omega-3 fatty acids, PCSK9 inhibitors (evolocumab, alirocumab), and/or fibrates can be considered in statin-intolerant patients or as complimentary therapy.
  • ACE inhibitor (ACEi) is recommended in all patients with ACS particularly in the presence of diabetes, LV dysfunction, or heart failure.
  • 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: enoxaparin or unfractionated heparin (UFH), fondaparinux, or bivalirudin. Bivalirudin has been associated with a lower bleeding risk.

Second Line

  • Nondihydropyridine calcium channel blocker (CCB) (verapamil or diltiazem) to reduce myocardial oxygen demand when β-blockers are contraindicated if left ventricular ejection fraction is normal. Use oral long-acting CCB only after β-blockers and nitrates have been fully used. Long-acting CCBs are recommended in treatment of patients with epicardial or microvascular coronary artery spasm. Avoid in patients with heart block.
  • Sublingual nitroglycerin as needed for angina; long-term nitrate therapy for recurrent angina
  • Ranolazine indicated in treatment of chronic angina not responsive to other medications at 500 to 1,000 mg, twice a day. Benzodiazepines in patients with cocaine/methamphetamine intoxication. Avoid β-blockers in patients who use cocaine or methamphetamine.

Issues For Referral

  • Cardiology consultation is indicated for NSTE-ACS. Patients will need close follow-up with a cardiologist.
  • Referral to exercise-based cardiac rehabilitation program prior to hospital discharge is associated with decreased morbidity and mortality. Referral to a dietitian should be considered.

Surgery/Other Procedures

  • Coronary reperfusion strategies include PCI with stenting and CABG surgery.
  • Mechanical circulatory support for patients with refractory shock

Admission, Inpatient, and Nursing Considerations

  • Admit patients with suspected NSTE-ACS.
  • Considerations in special populations
    • Older population (≥75 years)
      • Benefit of early invasive management in elderly ≥ young population
      • Pharmacotherapy should be individualized based on weight, baseline characteristics, and comorbidities.
    • Pregnancy: Specific risk factors for ACS in pregnancy include advanced maternal age, gestational diabetes, and preeclampsia/eclampsia. Spontaneous coronary artery dissection and thromboembolism should be considered in evaluation of pregnant women with ACS. ACEi, ARBs, and statins are contraindicated.

Ongoing Care

Follow-up Recommendations

  • Patients with low-risk suspected ACS who have normal serial ECGs and cardiac troponins may have a treadmill ECG, stress myocardial perfusion imaging, or stress echocardiography within 72 hours after discharge. Follow up 2 to 6 weeks (low risk) and 14 days (high risk).
  • Patients with LVEF <40% are at increased risk of ventricular arrhythmias. Repeat LVEF evaluation 1 to 3 months postdischarge to reassess function and determine the need for ICD implantation.


Diet relationship to CAD is complex; patients should maintain a diet low in saturated and trans fats, low in sodium, and high in fiber.

Patient Education

Education on diet, exercise, smoking cessation, and lifestyle modification. It is safe to resume exercise; sexual activity within 2 weeks in asymptomatic patients after outpatient reevaluation. Recommend pneumococcal and influenza vaccination.


UA/NSTEMI patients have lower in-hospital mortality than those with STEMI but a similar or worse long-term outcome.


Cardiogenic shock, heart failure, dysrhythmia (2), acute thromboembolic stroke, pericarditis/Dressler syndrome, depression (increases mortality risk)



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


  • 410.70 Subendocardial infarction, episode of care unspecified
  • 411.1 Intermediate coronary syndrome


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

Clinical Pearls

  • Dual antiplatelet therapy, antithrombotic therapy, β-blocker, high-dose statin therapy, and nitrates are the cornerstones of initial therapy and should be initiated promptly.
  • Duration of antithrombotic therapy after NSTEMI depends on type of stent received and medications administered.


Keith Ranney Love, MD, BA
Alejandro Folch Sandoval, MD
Colleen M. Harrington, MD, FACC, FASE


  1. Collet JP, Cuisset T, Rangé G, et al. Bedside monitoring to adjust antiplatelet therapy for coronary stenting. N Engl J Med. 2012;367(22):2100–2109. [PMID:23121439]
  2. Benjamin EJ, Virani SS, Callaway CW, et al; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67–e492. [PMID:29386200]

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