Unstable Angina

Etiology

Coronary atherosclerotic disease underlies unstable angina in nearly all patients with acute myocardial ischemia. The primary cause of unstable angina involves coronary artery narrowing due to a nonocclusive thrombus forming on a disrupted atherosclerotic plaque.[6] A less common cause is coronary artery vasospasm, as seen in variant Prinzmetal angina. Endothelial or vascular smooth muscle dysfunction triggers this vasospasm (see Image. Coronary Artery Changes and Corresponding Types of Angina).[7]

Epidemiology

Despite significant advancements in diagnosing and treating ACS, cardiovascular disease remains the leading cause of death worldwide, with ischemic heart disease accounting for 50% of these fatalities.[8] Atherosclerotic cardiovascular diseases contribute to 12% of the global annual loss in disability-adjusted life years.[9] Notable global variations exist in rates of revascularization and long-term mortality following ACS.[10][11]

Coronary artery disease (CAD) represents the most common form of atherosclerotic cardiovascular disease and caused approximately 371,506 deaths in 2022; adults younger than 65 accounted for 20% of cardiovascular disease deaths in the same year. Among adults aged 20 and older, 1 in 20 has CAD. Every 40 seconds, 1 person in the United States (US) experiences a heart attack. (Source: Centers for Disease Control and Prevention, 2024) CAD causes over a third of the deaths in individuals aged 35 and older, representing the leading cause of mortality in this age group.

Furthermore, approximately 18 million individuals in the US live with CAD. The incidence is higher in men but converges between men and women after the age of 75. Additional risk factors include the following:

• Obesity
• Diabetes
• Hypertension
• High cholesterol
• Tobacco use (smoking history)
• Cocaine or amphetamine abuse
• Family history of cardiovascular disease
• Chronic kidney disease
• Human immunodeficiency virus infection
• Autoimmune disorders
• Anemia [12] 

The mean age at presentation is 62 years, with women presenting at older ages than men, while Black individuals tend to present at a younger age. Heart disease accounted for 17.4% of all deaths in 2021. Among racial and ethnic groups, Black non-Hispanic individuals had the highest proportion at 22.6%, while Hispanic individuals had the lowest at 11.9%. Advancements in ACS management over the past 20 years have contributed to significant reductions in age-standardized mortality rates in higher-income regions such as North America, Europe, and Oceania, compared to persistently higher rates in lower-income areas, including Latin America, Asia, and the Caribbean.[13]

Pathophysiology

Unstable angina occurs when blood flow to the myocardium is obstructed, leading to inadequate perfusion.[14] Blood supply to the heart begins in the aorta and flows into the coronary arteries, which branch into smaller vessels to nourish specific areas of the myocardium. The left coronary artery divides into the circumflex and left anterior descending arteries, while the right coronary artery splits into smaller branches. Symptoms of angina develop when increased oxygen demand coincides with reduced coronary flow reserve, primarily caused by vessel lumen obstruction due to atherosclerotic coronary plaque or decreased oxygen supply. Some patients without significant coronary lesions on angiography may have anomalies in coronary circulation, coronary microvascular dysfunction, or vasospasm.[15]

Unstable angina typically results from the disruption of intraluminal plaque, leading to the formation of a nonocclusive thrombus. Factors that increase myocardial oxygen demand include the following:

• Arrhythmias
• Fever
• Hypertension
• Cocaine use
• Aortic stenosis
• Arteriovenous shunts
• Anemia
• Thyrotoxicosis
• Pheochromocytoma
• Congestive heart failure

Proinflammatory cytokines, including interleukin-6, interleukin-1β, tumor necrosis factor-α, C-reactive protein, and interleukin-17, are substantially elevated in the blood serum of patients with unstable angina. This finding suggests that the inflammatory process is activated in unstable angina.[16]

History and Physical

Patients often present with chest pain and shortness of breath. Chest pain typically presents as pressure-like but may also be described as tight, burning, or sharp. Patients frequently report discomfort rather than pain, which often radiates to the jaw or arms, affecting both the left and right sides. Constitutional symptoms such as nausea, vomiting, diaphoresis, dizziness, and palpitations may accompany these complaints. Exertion can worsen the pain, while rest, nitroglycerin, and aspirin may provide relief. Any pain, pressure, tightness, or discomfort in the chest, neck, arms, shoulders, upper abdomen, or back, along with fatigue and shortness of breath, should be considered anginal equivalents.[17]

A key distinguishing feature of unstable angina is incomplete resolution of pain with typical relieving factors. Many patients have preexisting CAD, either previously diagnosed or with stable anginal symptoms. These patients often report increased frequency, duration, or severity of chest pain episodes; such changes suggest unstable angina rather than stable or other causes of chest pain. Recognizing these symptoms is critical, as unstable angina may indicate impending myocardial infarction or ST-elevation myocardial infarction, necessitating urgent evaluation due to higher morbidity and mortality risks compared to stable angina.[18]

Physical examination findings typically lack specificity for diagnosing unstable angina. However, thorough patient evaluation remains essential for immediate risk assessment, detection of potential hemodynamic effects, and identification of mechanical complications.[19] Findings suggestive of high-risk status include the following:

• Dyskinetic apex
• Elevated jugular venous pressure
• Presence of third or fourth heart sounds (S3 or S4)
• New apical systolic murmur
• Rales and crackles
• Hypotension

Current guidelines recommend using risk-stratification tools to assess prognosis and guide management.[20] Commonly employed risk scores include the Thrombolysis in Myocardial Infarction risk score for non-ST-elevation myocardial infarction and the Global Registry of Acute Coronary Events risk score.[21][22]

Evaluation

Patients require rapid evaluation with an electrocardiogram (ECG) to assess for ischemic signs or a possible ST-segment elevation myocardial infarction (STEMI), alongside close monitoring of vital signs and oxygenation. ECG findings in unstable angina may include hyperacute T-waves, flattened or inverted T-waves, and ST depression. ST elevations indicate STEMI, necessitating treatment with percutaneous coronary intervention or thrombolytics while awaiting catheterization laboratory availability.

Arrhythmias associated with ACS include junctional rhythms, sinus tachycardia, ventricular tachycardia, ventricular fibrillation, and left bundle branch block. However, most patients, especially with unstable angina, remain in sinus rhythm, unlike those with infarcted tissue. No specific ECG changes definitively diagnose unstable angina. Many patients exhibit normal or nonspecific ST-T changes. Therefore, a normal or nonspecific ECG does not exclude unstable angina.

Laboratory evaluation should include a complete blood count to assess for anemia, a platelet count, and a basic metabolic profile to detect electrolyte abnormalities. High-sensitivity cardiac troponin testing is the standard for identifying myocardial infarction. Pro-brain natriuretic peptide levels may also be measured, as elevated values are associated with increased mortality risk. Coagulation studies are recommended when anticoagulation is planned or anticipated. A chest radiograph is often helpful in evaluating heart size and the mediastinum, aiding in the detection of other potentially serious causes of chest pain, such as aortic dissection.

The clinical history should be reviewed to rule out other emergent etiologies of chest pain or shortness of breath, including pulmonary embolism, aortic dissection, esophageal rupture, pneumonia, and pneumothorax. Continuous cardiac monitoring is essential for detecting rhythm disturbances. Further evaluation may involve cardiac stress tests, such as treadmill stress testing, stress echocardiography, myocardial perfusion imaging, or cardiac computed tomography or magnetic resonance imaging. Cardiac catheterization remains the gold standard.

These tests are typically ordered and performed by inpatient and primary care clinicians. However, with the expansion of observation medicine, emergency clinicians may also initiate them.[23][24] Urgent diagnostic testing is not recommended for patients with stable chest pain who are considered low risk. Still, those at intermediate or high risk should undergo cardiac imaging and further evaluation.

ACS risk assessment should include the following:

• Prior myocardial infarction or known history of coronary artery disease
• Transient ECG or hemodynamic changes during chest pain
• Chest, neck, or left arm consistent with angina
• ST depression or elevation of more than 1 mm
• Marked symmetrical T-wave inversion

These features raise the likelihood of ACS and should prompt expedited diagnostic and therapeutic decision-making. Recognizing these signs early is essential to reduce morbidity and mortality.

Treatment / Management

Management primarily aims to increase blood flow in the coronary arteries through diverse modalities. Treatment strategies should be tailored to the patient’s risk profile, symptom severity, and overall clinical presentation.

Antiplatelet Agents

Effective management of ACS requires prompt initiation of antiplatelet therapy to inhibit platelet activation and reduce clot progression. Aspirin combined with oral P2Y12 inhibitors remains the standard regimen to lower major adverse cardiovascular events (MACE).

Aspirin

Aspirin is commonly administered for its antiplatelet effects, typically at a dose of 162 to 325 mg orally or 300 mg rectally if swallowing is not possible. Administration should occur within 30 minutes of presentation.

Ticagrelor

For patients with confirmed ACS, ticagrelor is administered as a 180-mg loading dose as early as possible, along with aspirin, followed by a maintenance dose of 90 mg orally twice daily for 12 months. After 12 months, the dose may be reduced to 60 mg twice daily, except in patients at high ischemic risk, who should continue 90 mg twice daily.

Prasugrel

Prasugrel is administered as a 60-mg oral loading dose before percutaneous coronary intervention in combination with aspirin, then maintained at 10 mg daily. For patients weighing less than 60 kg, the maintenance dose should be reduced to 5 mg daily. Prasugrel is contraindicated in patients with a history of transient ischemic attack or stroke due to poorer outcomes.

Clopidogrel 

Clopidogrel is preferred for patients who have a high bleeding risk or are receiving concomitant anticoagulation therapy. The usual dose is 75 mg orally once daily, with an optional 300 mg loading dose administered before PCI in ACS.

Choice of antiplatelet agent

In all patients with ACS, an oral P2Y12 inhibitor should be used in conjunction with aspirin to reduce MACE. For patients with non-ST-segment elevation ACS (NSTE-ACS) undergoing PCI, either ticagrelor or prasugrel is recommended. Ticagrelor is preferred for patients with NSTE-ACS who are managed without planned invasive intervention to reduce MACE. Among patients with ACS undergoing percutaneous coronary intervention, prasugrel may be favored over ticagrelor. When ticagrelor or prasugrel are unavailable, contraindicated, or not tolerated, clopidogrel serves as the recommended alternative.

Duration of therapy

Combination therapy with aspirin and an oral P2Y12 inhibitor is recommended for at least 12 months in patients without significant bleeding risk. Regular reassessment is necessary to balance bleeding and ischemic risks.

Special considerations

Patients at high risk of gastrointestinal bleeding should receive oral proton pump inhibitors. For patients requiring long-term anticoagulation for other conditions, aspirin may be discontinued 1 to 4 weeks after percutaneous coronary intervention, while continuing P2Y12 inhibitor therapy, preferably with clopidogrel. Ticagrelor monotherapy for 1 month or longer after PCI is advised for patients who have tolerated dual antiplatelet therapy with ticagrelor.

Nitroglycerin Administration

Nitroglycerin is available in multiple formulations—intravenous, sublingual, transdermal, and oral—and acts by dilating coronary arteries to enhance blood flow and lower blood pressure. This vasodilation reduces myocardial workload and oxygen demand, helping to relieve ischemic symptoms.

Supplemental Oxygen Therapy

Supplemental oxygen should be administered via nasal cannula to maintain adequate oxygen saturation. These 3 interventions—nitroglycerin, oxygen, and initial assessment—are critical for the rapid evaluation and management of unstable angina. Patients with persistent pain or delayed recovery require close monitoring, as they face a higher risk of progression to myocardial infarction.

Other Modalities

Other therapeutic modalities for unstable angina extend beyond the initial management strategies and include several pharmacologic and procedural options. Anticoagulation with either low- or high-molecular-weight heparin is commonly employed to prevent thrombus formation. β-blockers play a crucial role in reducing myocardial energy demand by lowering both heart rate and blood pressure.[25][26] Ranolazine has been studied in patients with unstable angina, showing a significant reduction in recurrent ischemia, making it a valuable adjunctive treatment.[27](A1)

Lipid-lowering therapy is a cornerstone in the management of ACS, with high-intensity statins recommended for all patients. Suppose low-density lipoprotein cholesterol (LDL-C) goals—typically equal to or less than 70 mg/dL—are not achieved with statins alone. In that case, additional agents such as ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors should be introduced. Ezetimibe, when added to statin therapy, has demonstrated reductions in LDL-C and a decreased risk of major cardiovascular events, including nonfatal myocardial infarction, stroke, and unstable angina requiring rehospitalization or revascularization. PCSK9 inhibitors, such as alirocumab, evolocumab, and inclisiran, are reserved for patients who do not reach LDL-C targets despite receiving maximal statin and ezetimibe therapy.

Cardiac angiography plays a crucial role in the management of unstable angina, especially for patients with elevated risk scores or clinical indicators such as cardiogenic shock, depressed ejection fraction, angina refractory to medical therapy, new mitral regurgitation, or unstable arrhythmias. Early percutaneous coronary intervention in NSTEMI, typically within 6 hours, has been associated with lower mortality compared to delayed intervention. Additionally, patients with unstable angina undergoing percutaneous coronary intervention report significant improvements in quality of life by 3 months postprocedure compared to 1 month.[28](B2)

Differential Diagnosis

The differential diagnosis for unstable angina is broad and includes both cardiac and noncardiac conditions. Careful assessment is essential to avoid misdiagnosis and ensure appropriate management. Clinical entities that can mimic unstable angina include the following:

• Aortic dissection
• Pericarditis
• Pneumothorax
• Pulmonary embolism
• Peptic ulcer disease
• Pneumonia
• Myocarditis
• Gastroesophageal reflux disease
• Costochondritis
• Muscle spasm
• Panic attack

Accurate differentiation among these conditions is vital to guide urgent management and reduce the risk of adverse outcomes. Prompt identification ensures that life-threatening conditions such as aortic dissection or pulmonary embolism are not overlooked.

Prognosis

The critical complications of unstable angina include the following:

• Myocardial infarction 
• Heart failure
• Ventricular arrhythmia 
• Cardiac arrest

Study results indicate that patients with new-onset ST-segment elevation greater than 1 mm have a 12-month myocardial infarction or mortality rate of approximately 11%, compared to 7% among those with isolated T-wave inversion. Adverse prognostic factors include the following:

• Low ejection fraction
• Ongoing congestive heart failure 
• New or worsening mitral regurgitation
• Hemodynamic instability
• Sustained ventricular tachycardia
• Recurrent episodes of angina despite maximal therapy

The atherogenic index of plasma, calculated as the logarithm (base 10) of the ratio of triglycerides to high-density lipoprotein cholesterol, serves as a novel biomarker for assessing the risk of coronary heart disease and atherosclerosis.[29] In patients with prediabetes, the atherogenic index of plasma demonstrates a significant correlation with the prognosis of unstable angina.[30] Additionally, exposure to specific air pollutants, particularly carbon monoxide and particulate matter with a diameter of 10 µm or less, has been associated with an increased risk of heart failure readmissions among patients with unstable angina.[31]

Complications

Although unstable angina is associated with lower mortality and relative incidence than NSTEMI, the risk of subsequent nonfatal myocardial infarction remains comparable.[32] Patients with unstable angina demonstrate a lower 1-year risk of death and MACE than those with NSTEMI. However, when compared to patients with stable angina undergoing coronary angiography without a prior history of coronary artery disease, unstable angina is associated with a nonsignificant difference in MACE risk but a higher risk of death.[33]