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) 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 ECG, or imaging evidence of loss of viable myocardium or 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 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 (1).
  • In United States, average age at first MI is 65.6 years for males and 72.0 years for females (1).
  • Incidence of MI is higher in blacks across all age groups as compared to the white population, with the highest incidence in black males (1).

  • An estimated 16.5 million Americans ≥20 years have coronary artery disease (CAD) with the overall prevalence of MI being 3.0% (3.8% for males and 2.3% for females) (1).
  • Mortality
    • CAD is the leading cause of death in adults in the United States with overall age-adjusted mortality of 98.8/100,000 (1).
    • Death rate is higher in men as compared to women and in blacks as compared to whites (1).

Etiology and Pathophysiology

  • NSTE-ACS occurs primarily due to a sudden decrease in myocardial blood flow due to acute plaque rupture or plaque erosions leading to partially occluding thrombosis.
  • Other mechanisms include:
    • Dynamic obstruction triggered by intense spasm of a coronary artery (Prinzmetal angina or coronary vasospasm induced by cocaine or methamphetamine)
    • Increased myocardial oxygen demand resulting in supply–demand mismatch, microcirculatory dysfunction without epicardial coronary obstruction
    • Less common causes include coronary arterial inflammation, dissection/rupture, thromboembolism.

  • Chromosome 9p21.3 has been the most frequently associated genetic marker for MI in European-derived populations and is also associated with coronary heart disease in patients of East Asian descent (1).
  • Furthermore, chromosome 9p21.3 has been associated with premature atherosclerosis, peripheral arterial disease, heart failure, ischemic stroke, and aortic aneurysm (1).

Risk Factors

  • Traditional/classic
    • Age (strongest risk factor), male gender, prior MI, hypertension, tobacco use, diabetes mellitus (DM), dyslipidemia, and family history of premature CAD (Premature CAD is 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, higher intake of red meat, radiation exposure

General Prevention

  • Smoking cessation, healthy diet, weight control, physical activity
  • Risk factor control: diabetes and blood pressure control, lipid-lowering therapy (statins), daily aspirin (in select patients)

Commonly Associated Conditions

  • Vascular disease (cerebrovascular and peripheral vascular disease, aneurysms, erectile dysfunction)
  • Other forms of heart disease (heart failure, valvular disease, high-output states)
  • Disease related to underlying risk factors: chronic obstructive pulmonary disease and thrombophilic disorders



  • Chest heaviness/tightness lasting ≥10 minutes; occurs with or without exertion, may increase in frequency. 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 with symptoms such as dyspnea, diaphoresis, and extreme fatigue which represent “anginal equivalents.”
  • Risk factors for CAD
  • Use of cocaine or amphetamines

Physical Exam

  • General: abnormal vital signs including tachycardia or bradycardia, hypertension or hypotension, widened pulse pressure, tachypnea, fever, transverse ear crease, poor dental hygiene, stigmata of tobacco use
  • Cardiovascular: dysrhythmia, jugular venous distention (JVD), new murmur, rub or gallop, diminished peripheral pulses, carotid bruits
  • Respiratory: tachypnea, ↑ work of breathing, crackles
  • Neurologic: fatigue, weakness, altered mental status
  • 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/tamponade, heart failure, hypertensive emergency, stress cardiomyopathy (Takotsubo), dysrhythmia, and mitral valve disease
  • Pulmonary: pulmonary embolism, pneumothorax, pneumonia, pleuritis, bronchitis
  • Panic disorder and anxiety disorders
  • Musculoskeletal pain: costochondritis, rib fracture
  • GI: gastroesophageal reflux disease (GERD), 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.
  • Complete blood count, bone morphogenic proteins, and serum biomarker (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.
    • With contemporary troponin assays, older cardiac markers of injury-like lactate dehydrogenase, creatine kinase-MB (CK-MB), and myoglobin are much less sensitive and specific and have limited utility in the routine management of ACS. CK-MB has been shown to have better specificity than troponins in post-PCI MI.
    • Patients with negative biomarkers within 6 hours of the onset of symptoms should have biomarkers remeasured 8 to 12 hours from onset of symptoms.
  • Chest x-ray, computed tomography with contrast to exclude other etiologies
  • Transthoracic echocardiography is recommended to assess for regional wall motion abnormalities, systolic function, and to exclude alternate etiologies.

Follow-Up Tests & Special Considerations
  • Fasting lipid profile, preferably within 24 hours
  • Activated partial thromboplastin time (aPTT)
  • Urine drug screen in selected patients
  • TSH if symptoms of hyperthyroidism
  • Other lab tests: B-type natriuretic peptide or N-terminal pro–B-type natriuretic peptide; increases with MI and may not indicate heart failure
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, stress echocardiography, or nuclear stress study.
  • Alternatively, coronary computed tomography angiography can be performed as well to exclude NSTE-ACS.


General Measures

  • Risk stratify using 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
  • Avoid continuation of NSAIDs.
  • Deep vein thrombosis prophylaxis
  • Smoking cessation
  • Correction of 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 OR
    • Prasugrel 60 mg PO, followed by 10 mg PO daily. 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.
    • 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 less than 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.
  • 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 beta-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 or atenolol 25 to 50 mg twice daily. 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.
  • 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 normal ejection fraction (EF). 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 coronary artery spasm. Avoid in patients with heart block.
  • Long-term nitrate therapy for recurrent angina/ischemia or heart failure
  • Sublingual nitroglycerin at discharge
  • Ranolazine indicated in treatment of chronic angina not responsive to other meds; 500 to 1,000 mg, twice a day
  • Benzodiazepines in patients with cocaine/methamphetamine intoxication. Avoid β-blockers in cocaine or methamphetamine users.

Issues For Referral

  • Cardiology consultation is appropriate for NSTE-ACS.
  • Patients will need close follow-up with a cardiologist.
  • Referral to exercise-based cardiac rehabilitation program prior to hospital discharge

Surgery/Other Procedures

  • Coronary reperfusion strategies include:
    • PCI with stent placement
    • CABG surgery
  • Intra-aortic balloon pump for patients may be performed with refractory symptoms/shock

Admission, Inpatient, and Nursing Considerations

  • Admit patients with risk factors who present with chest pain and 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 and renal function.
    • 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

  • It is reasonable in patients with suspected ACS (low risk) who have normal serial ECGs and cardiac troponins to have a treadmill ECG, stress myocardial perfusion imaging, or stress echocardiography before or within 72 hours after discharge.
  • Follow up 2 to 6 weeks (low risk) and 14 days (high risk).
  • All patients with reduced EF need reevaluation for implantable cardioverter defibrillator placement for primary prevention >40 days to 3 months (postrevascularization) after discharge.


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, mitral regurgitation, ventricular aneurysm, dysrhythmia, acute pulmonary embolism, 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

  • Discontinue NSAIDs, nonselective or selective cyclooxygenase (COX)-2 agents, except for acetylsalicylic acid, due to increased risks of mortality, reinfarction, hypertension, heart failure, and myocardial rupture.
  • Discontinue clopidogrel or prasugrel or ticagrelor 5 to 7 days before elective CABG.
  • Dual anti-platelet 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.
  • Avoid β-blockers in cocaine or methamphetamine users.


Shawn J. John, MBBS, BSc Hons
Naureen Bashir Rafiq, MD


  1. Benjamin EJ, Virani SS, Callaway CW, et al; for 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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