Non–ST-Segment Elevation Myocardial Infarction (NSTEMI) and Unstable Angina (UA)

Clinical Features and Natural HistoryTop

Unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI) are 2 of 3 acute coronary syndromes (ACSs) (see Acute Coronary Syndrome) associated with myocardial ischemia. They are caused by a plaque rupture and thrombosis mechanism. UA and NSTEMI differ slightly in their diagnostic criteria, but they have similar management approaches. The third type of ACS, ST-segment elevation myocardial infarction (STEMI), is discussed separately (see ST-Segment Elevation Myocardial Infarction).

1. Symptoms: Chest pain or equivalent ischemic discomfort (features: see Stable Angina Pectoris). Unlike in stable coronary artery disease (CAD), the pain is not relieved within 5 minutes of removing the precipitating factors or administering sublingual nitrate, but it lasts longer and may occur at rest. Note that in women, patients with diabetes, and the elderly angina may manifest as dyspnea or epigastric discomfort—an anginal equivalent.

2. Classification of pain in unstable angina (UA)/non–ST-segment elevation myocardial infarction (NSTEMI):

1) Angina occurring at rest, lasting >20 minutes.

2) New-onset angina within the prior month, Canadian Cardiovascular Society (CCS) class III (see Table 1 in Stable Angina Pectoris).

3) Angina with a crescendo pattern: Angina that is becoming more frequent, is caused by less intense physical exertion than previously, lasts longer, has increased by at least one CCS class, and is at least CCS class III.

DiagnosisTop

Clinicians should assess the likelihood that the patient's signs and symptoms represent an ACS. This is an important step in the assessment, as it helps avoid unnecessary invasive procedures and treatments in patients with a low pretest probability of ACS.

ACS refers specifically to ischemia caused by plaque rupture and thrombosis of the affected coronary artery. It includes UA, NSTEMI, and STEMI as diagnostic possibilities. A patient with an elevated cardiac troponin level >99th percentile of normal is said to have a myocardial infarction (MI), as long as they have other features consistent with ischemia, and cannot be diagnosed with just UA (see Acute Coronary Syndrome; see Table 1 in Ischemic Heart Disease).

Patients who have troponin elevations without other features of ischemia (eg, new regional wall motion abnormality, angiographic stenosis, typical electrocardiographic changes) are diagnosed with myocardial injury. If such features are present, then patients are diagnosed with MI. The category of MI covers several types. Type 1 MI is defined as tissue infarction due to the aforementioned plaque rupture and coronary thrombosis. Type 2 MI, clinically termed “demand ischemia,” is secondary to oxygen supply and demand mismatch and has a multitude of mechanisms such as hypoxia, hypotension, vasospasm, and coronary dissection. As such, patients without any underlying CAD may have type 2 MI. Differentiating between the 2 types of MI is important, as management approaches are very different. For instance, patients with type 2 MI will likely not benefit from antiplatelet therapy targeted against thrombus formation, whereas this is a cornerstone of medical management for those with type 1 MI.

Patients with a history of obstructive CAD have a higher likelihood of ACS symptoms than patients with risk factors known to be associated with CAD, such as dyslipidemia and smoking.

Once the diagnosis of ACS is established, the second step is to assess the risk of adverse events from the ACS. Standardized risk scores are available, for instance, the Global Registry of Acute Coronary Events (GRACE) score (Table 1) or the Thrombolysis in Myocardial Infarction (TIMI) NSTEMI score (available at www.timi.org). These tools estimate the risk of mortality and recurrent ischemia from UA/NSTEMI and therefore facilitate the risk stratification process, which guides the subsequent management.

Definition of MI: see Table 1 in Ischemic Heart Disease.

Diagnostic Tests

1. Resting electrocardiography (ECG) (Figure 1): Abnormalities may be observed in ≥2 contiguous leads (groups of contiguous leads include: V1-V6, anterior leads; II, III, aVF, inferior leads; I, aVL, lateral/apical leads; V3R, V4R, supplemental leads covering the free wall of the right ventricle).

1) ST-segment depression (less commonly, transient ST-segment elevation): Abnormalities of diagnostic value are new horizontal or downsloping ST-segment depressions ≥0.05 mV.

2) T-wave inversion (>0.1 mV; inversions ≥0.2 mV are associated with higher risk) or reversal of a prior T-wave inversion. T-wave flattening is relatively nonspecific.

3) ECG is normal in 30% to 50% of patients.

2. Blood tests: Patients have elevated serum markers of myocardial necrosis in NSTEMI (the markers may also be elevated in UA, but in such cases they do not exceed the acute MI cutoff values, >99th percentile of the upper limit of normal [ULN]):

1) Cardiac-specific troponin T (cTnT), troponin I (cTnI), or high-sensitivity troponin I or T.

2) Creatine kinase MB subunit (CK-MB) concentration (CK-MBmass) >510 microg/L (depending on the assay); this is used only when cardiac-specific troponin measurements are not available.

3. Chest radiography may reveal signs of other diseases that may have caused angina or features of heart failure. Noticing an abnormal width of mediastinum should prompt consideration of aortic dissection.

4. Resting echocardiography may reveal regional wall motion abnormalities consistent with regional ischemia or support other etiologies of chest pain, such as aortic stenosis or hypertrophic cardiomyopathy. Decreased ejection fraction (<50%) is also helpful to document, as it portends a worse prognosis and changes management.

5. Coronary angiography (Figure 1) reveals lesions located in the coronary arteries that are responsible for the clinical picture (usually arterial occlusion) and determine the optimal form of revascularization, either percutaneous coronary intervention (PCI) or surgical coronary artery bypass graft (CABG) surgery. Routine coronary angiography has been shown to be beneficial in reducing recurrent ischemia and death in patients at moderate to high risk and should be performed.

Differential Diagnosis

In patients presenting with acute chest pain, differential diagnosis includes (but is not limited to) aortic dissection, pulmonary embolism, myopericarditis, musculoskeletal chest pain, and gastroesophageal disease.

Other Diagnostic Considerations

Traditionally, the term “myocardial infarction” has not included elevation in cardiac biomarkers in the setting of renal failure, heart failure, cardioversion, ablation, sepsis, myocarditis, cardiotoxic medications, or malignancy. There are situations where MI may occur outside of an acute plaque rupture event, such as in the setting of CABG and PCI (see Table 1 in Ischemic Heart Disease). Both NSTEMI and STEMI may occur in such settings.

1. Percutaneous coronary intervention (PCI)-related MI: Elevation in troponin values (>5 × 99th percentile of the upper reference limit [URL]) in patients with normal baseline values (≤99th percentile of URL) or a rise in troponin values >20% (if the baseline values are elevated and are stable or falling) plus signs of myocardial ischemia or evidence of ischemia found on ECG, angiography, or imaging.

2. MI associated with CABG: Elevation in troponin values (>10 × 99th percentile of URL) in patients with normal baseline troponin values (≤99th percentile of URL), plus new pathologic Q waves or new left bundle branch block, an angiographically documented new graft or a new native coronary artery occlusion, or imaging evidence of a new loss of viable myocardium.

TreatmentTop

General Considerations

Treatment of high-risk patients is conducted optimally in an intensive cardiac care or coronary care unit or equivalent; high-risk patients can be transferred to a non–intensive care ward >24 hours of being free from chest pain, significant arrhythmias, and hemodynamic instability.

1. Monitoring: Continuous ECG monitoring (telemetry) for 24 hours after admission and further monitoring depending on clinical status and ongoing ischemia.

2. Assess the risk of death or MI using risk scores, for instance, GRACE (Table 1) or TIMI (visit www.timi.org). Treatment is tailored to the patient’s risk of adverse events (Figure 2):

1) High-risk patients (GRACE score >140, a defined increase in troponin levels, or dynamic ST-segment or T-wave changes) and intermediate-risk patients (recurrent symptoms or additional high-risk factors) without contraindications for invasive procedures benefit from a routine coronary angiography, which is recommended. For example, a man aged 75 years with ST-segment deviation and elevated creatinine and troponin levels would fit in this high-risk category.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005 Jun 15;293(23):2908-17. PubMed PMID: 15956636. High-risk patients (GRACE score >140) should have an early invasive approach (ie, within 24 hours if possible).Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Mehta SR, Granger CB, Boden WE, et al; TIMACS Investigators. Early versus delayed invasive intervention in acute coronary syndromes. N Engl J Med. 2009 May 21;360(21):2165-75. doi: 10.1056/NEJMoa0807986. PubMed PMID: 19458363. Patients with refractory or recurrent angina despite maximal medical therapy with nitroglycerin, heart failure, hemodynamic instability (shock), mechanical complications, or life-threatening arrhythmias (ventricular fibrillation or ventricular tachycardia) should undergo an early invasive approach as well.

2) Low-risk patients are those with no recurrent chest pain, without symptoms of heart failure, without abnormal ECG findings, and with normal cardiac troponin (or any other appropriate marker of myocardial necrosis) levels. The determination should be made whether these symptoms are related to ACS or a noncardiac cause. Low-risk patients may have a noninvasive assessment (ie, nuclear myocardial perfusion imaging or exercise treadmill testing), and if it is normal or low risk, they may be treated medically. Low-risk patients with the classical description of low-threshold angina should undergo an invasive assessment.

3. Oxygen should be administered to each patient with hypoxia (arterial saturation <90%). Monitor saturation using pulse oximetry and assess blood gases in patients with abnormal results. The use of oxygen in patients without hypoxia may be detrimental.Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness of populations and outcome measures. Stub D, Smith K, Bernard S, et al; AVOID Investigators. Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction. Circulation. 2015 Jun 16;131(24):2143-50. doi: 10.1161/CIRCULATIONAHA.114.014494. PubMed PMID: 26002889.

4. Supportive medical management: A potassium concentration >4.0 mEq/L and magnesium concentration >1 mmol/L may prevent atrial and ventricular dysrhythmias. Patients with anemia may benefit from packed red blood cell transfusion to target hemoglobin concentration >80 g/L, especially if ischemia is ongoing. Patients receiving nonsteroidal anti-inflammatory drugs (NSAIDs) other than acetylsalicylic acid (ASA) should have this therapy discontinued.

Anti-Ischemic Treatment and Plaque Stabilization

1. Nitrates can be used to relieve chest pain and are for symptomatic use only. Sublingual nitroglycerin can be given to acutely relieve chest pain but if the chest pain is ongoing, IV nitroglycerin can be considered (starting infusion rate of 5-10 microg/min, increased by 5-20 microg/min every 3 to 5 minutes until the resolution of pain or development of adverse effects [headache or hypotension]). Dosage, contraindications, and adverse effects: see Stable Angina Pectoris.

2. Beta-blockers should be used in patients to relieve angina and should be considered in all cases unless a contraindication exists (resting bradycardia, active wheezing). Caution should be exercised with use in patients with evidence of or at risk of developing cardiogenic shock. It should be strictly avoided in such patients.Evidence 4Strong recommendation (downsides clearly outweigh benefits; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Bangalore S, Makani H, Radford M, et al. Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med. 2014 Oct;127(10):939-53. doi: 10.1016/j.amjmed.2014.05.032. PubMed PMID: 24927909. Oral dosage, contraindications, and adverse effects: see Stable Angina Pectoris.

3. Calcium channel blockers, especially non-dihydropyridines diltiazem and verapamil, are indicated in patients with persistent or recurrent myocardial ischemia in whom beta-blockers are contraindicated. They should not be used in patients with left ventricular dysfunction. If treatment with nitrates and beta-blockers at the highest tolerated doses does not control ischemia, a long-acting dihydropyridine calcium channel blocker such as amlodipine may be added. Diltiazem or verapamil should not be combined with beta-blockers as the risk of atrioventricular block is high with this regimen. Dosage, contraindications, and adverse effects: see Stable Angina Pectoris.

4. Angiotensin-converting enzyme inhibitors (ACEIs): Starting an ACEI within 24 hours is indicated in all patients with no contraindications.Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20;342(3):145-53. Erratum in: 2000 May 4;342(18):1376. N Engl J Med 2000 Mar 9;342(10):748. PubMed PMID: 10639539. In case of ACEI intolerance, an angiotensin receptor blocker (ARB) may be used. Drugs: see Table 5 in Essential Hypertension; dosage: see Table 4 in Stable Angina Pectoris.

5. Morphine: In patients with persistent and moderate to severe pain despite the above treatments, 2 to 4 mg of IV morphine may be used.

6. Statins should be used in every patient unless contraindicated, regardless of the plasma cholesterol levels, optimally within 1 to 4 days of admission. Target low-density lipoprotein cholesterol (LDL-C) levels are <1.8 mmol/L (70 mg/dL) or a 50% reduction from baseline levels. Of note, recent Society of Cardiology (ESC) guidelines suggest an even lower target of 1.4 mmol/L (55 mg/dL). High-dose statins should be used to prevent recurrent events.Evidence 6Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Cannon CP, Braunwald E, McCabe CH, et al; Pravastatin or Atorvastatin Evaluation and In-fection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004 Apr 8;350(15):1495-504. Erratum in: N Engl J Med. 2006 Feb 16;354(7):778. PubMed PMID: 15007110. Of note, in a longer-term management in patients not meeting the above lipid targets despite statin therapy or in those who have intolerances to statin therapy, the addition of ezetimibe has cardiovascular benefit. More recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as potent therapies in patients with established cardiovascular disease and LDL-C levels >1.8 mmol/L (1.4 mmol/L according to ESC guidelines), both with and without statin therapy. Though PCSK9 inhibitors are well tolerated and effective, access to them may be limited by high cost.

Antithrombotic Therapy (Antiplatelet Agents and Anticoagulants)

Agents and dosage: Table 2.

1. Antiplatelet therapy:

1) ASA is used in all patients suspected of ACS unless contraindicated.Evidence 7Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988 Aug 13;2(8607):349-60. PubMed PMID: 2899772. In patients with documented aspirin allergy, a desensitization protocol could be used.

2) P2Y12 inhibitor therapy should be used in combination with ASA for 12 months. Ticagrelor or clopidogrel should be given, starting with a loading dose; the decision may be based on the patient’s underlying bleeding risk. Of note, prasugrel is currently not available in Canada. Although patients with STEMI generally always receive upfront dual antiplatelet therapy (DAPT), in NSTEMI/UA the decision can be more granular. Patients suspected of having surgical CAD should receive therapy in conjunction with consultation with the interventional cardiologist, as clopidogrel or sometimes no DAPT may be appropriate until coronary anatomy is delineated. In a direct comparison, ticagrelor was associated with a reduced rate of death, MI, and stroke but an increased rate of non-CABG major bleeding.Evidence 8Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Wallentin L, Becker RC, Budaj A, et al; PLATO Investigators, Freij A, Thorsen M. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. doi: 10.1056/NEJMoa0904327. PubMed PMID: 19717846. At the time of PCI, prasugrel can be used in addition to aspirin in patients without an increased risk of bleeding, without a history of ischemic stroke, with weight >60 kg, and aged <75 years.Evidence 9Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Wiviott SD, Braunwald E, McCabe CH, et al; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007 Nov 15;357(20):2001-15. PubMed PMID: 17982182. For patients who do have surgical disease on coronary angiography, discontinue clopidogrel or ticagrelor for 5 days and prasugrel for 7 days prior to CABG, unless the benefits of urgent revascularization outweigh the risks bleeding. Ticagrelor and prasugrel should not be used in patients with a history of hemorrhagic stroke or advanced liver disease.

2. Anticoagulant therapy should be used in every patient with a documented ACS before angiography. Options for anticoagulant therapy include fondaparinux (2.5 mg subcutaneously daily),Evidence 10Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006 Apr 6;354(14):1464-76. PubMed PMID: 16537663. enoxaparin (1 mg/kg subcutaneously bid),Evidence 11Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999 Oct 12;100(15):1593-601. PubMed PMID: 10517729. or IV unfractionated heparin (UFH).Evidence 12Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Collins R, MacMahon S, Flather M, et al. Clinical effects of anticoagulant therapy in suspected acute myocardial infarction: systematic overview of randomised trials. BMJ. 1996 Sep 14;313(7058):652-9. PubMed PMID: 8811758; PubMed Central PMCID: PMC2351968. In a direct comparison, fondaparinux was associated with a reduced major bleeding risk compared to enoxaparin.Evidence 13High Quality of Evidence (high confidence that we know true effects of the intervention). Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators, Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006 Apr 6;354(14):1464-76. PubMed PMID: 16537663. Other options include dalteparin, nadroparin, and bivalirudin (Table 2). Anticoagulant therapy is usually discontinued after PCI unless there are additional indications, such as increased risk of thromboembolism. In patients receiving conservative treatment, anticoagulant therapy may be continued until discharge or to a maximum of 8 days, whichever comes first. In patients already receiving anticoagulant therapy with warfarin or a direct oral anticoagulant (DOAC), these medications should be withheld on admission with a goal of transition to a heparinoid agent to facilitate cardiac catheterization if required.

Management After the Acute Phase

In patients with ongoing angina after medical treatment, perform coronary angiography with no prior noninvasive studies.

Follow-UpTop

Long-term follow-up is similar as in patients with stable angina (see Stable Angina Pectoris).

Secondary PreventionTop

1. Control of risk factors of atherosclerosis (see Prevention of Cardiovascular Diseases).

2. Cardiac rehabilitation: Evidence for the benefit of an exercise-based cardiac rehabilitation program is the greatest in patients with prior MI or revascularization, for whom a meta-analysis demonstrated reduction in cardiovascular death and hospitalization.Evidence 14Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). Anderson L, Oldridge N, Thompson DR, et al. Exercise-Based Cardiac Rehabilitation for Coronary Heart Disease: Cochrane Systematic Review and Meta-Analysis. J Am Coll Cardiol. 2016 Jan 5;67(1):1-12. doi: 10.1016/j.jacc.2015.10.044. PMID: 26764059. Of note, the benefit was not numerically lower if the intervention was performed in patients treated at home and involved only an exercise program.

3. Pharmacotherapy (specific indications, including antiplatelet agents [ASA and/or clopidogrel or prasugrel or ticagrelor], beta-blockers, ACEIs [or ARBs], aldosterone antagonists, statins: see Table 6 in ST-Segment Elevation Myocardial Infarction).

4. Anticoagulant treatment is recommended after coronary stenting in patients with atrial fibrillation and a moderate to high risk of stroke (CHADS₂ score ≥1) or for those with an additional indication for anticoagulation, such as recent venous thromboembolism. Treatment with a DOAC is preferred over warfarin according to the 2018 CCS antiplatelet guidelines. Ticagrelor or prasugrel should not be used for DAPT in this context. DAPT with a DOAC (triple therapy) can be continued for a period of 1 to 365 days, depending on clinical assessment of the bleeding and thrombotic risk ratio. After this period, dual therapy with clopidogrel plus DOAC without ASA for up to 1 year has been shown to be associated with reduced bleeding compared with triple therapy and should generally be considered. After one year, the use of a DOAC alone may be employed for stable CAD.Evidence 15Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Lou B, Liang X, Wu Y, et al. Meta-Analysis Comparing Dual Versus Single Antiplatelet Therapy in Combination With Antithrombotic Therapy in Patients With Atrial Fibrillation Who Underwent Percutaneous Coronary Intervention With Stent Implantation. Am J Cardiol. 2018 Aug 15;122(4):604-611. doi: 10.1016/j.amjcard.2018.04.050. Epub 2018 May 15. Review. PubMed PMID: 30205887. Siddiqui WJ, Khan MY, Rawala MS, et al. Anti-thrombotic therapy strategies with long-term anticoagulation after percutaneous coronary intervention - a systematic review and meta-analysis. J Community Hosp Intern Med Perspect. 2019 Jun 19;9(3):203-210. doi: 10.1080/20009666.2019.1611330. eCollection 2019. PubMed PMID: 31258858; PubMed Central PMCID: PMC6586086.

Tables and FiguresTop

Figure 3.11-1. Resting electrocardiography (ECG) of a 67-year-old woman during a chest pain episode (A; ST-segment depression in leads II, III, aVF, and V4 through V6) and after pain resolution (B). Coronary angiography showed stenoses (arrows) at the origin of the left anterior descending artery (80%), in the left circumflex artery (90%; C), and in the right coronary artery (90%; D).

Figure 3.11-2. Management algorithm of unstable angina or non–ST-segment elevation myocardial infarction.