Chronic stable angina

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-In-Chief: Maheep Singh Sangha, M.B.B.S.; Cafer Zorkun, M.D., Ph.D. [4] Muhammad Saad, M.B.B.S.[5]

Angina pectoris, commonly known as angina, is chest pain^[1] due to ischemia (a lack of blood and subsequent lack of oxygen supply) of the heart muscle. It is most often due to obstruction or spasm of the coronary arteries (the heart’s blood vessels). Coronary artery disease, also referred to as atherosclerosis of the coronary arteries, is the most common cause of angina. The term derives from the Greek ankhon (“strangling”) and the Latin pectus (“chest”) meaning “a strangling feeling in the chest”. In angina pectoris, symptomatic onset may include chest discomfort indicated by a feeling of tightness, heaviness, or pain in the chest cavity.

Chronic stable angina is a form of chest pain characterized by an insufficient blood flow to the myocardium of the heart to match myocardial energy demands (ischemia). The term angina was originally derived from the Greek word ankhon and the Latin word pectus, which when combined, loosely translates as “a strangling feeling in the chest”. Attempts to classify this disease state began as early as the 4th century B.C., when Lucius Annaeus Seneca first described the symptoms he was experiencing as “to have any other malady is to be sick; to have this is to be dying”. Throughout history many renowned researchers and health care professionals have contributed to the understanding, definition, and recognition of angina.

Angina pectoris is a sensation of chest discomfort that is often described as: a feeling of tightness, heaviness, or pain. Angina pectoris is a characteristic of coronary heart disease. When it occurs chronically, this is referred to as stable angina.

Walk through angina is the appearance of anginal chest discomfort early in the course of exertion which subsequently subsides despite continued exertion.

Mixed or variable threshold angina pectoris is a syndrome in which there is substantial variation in the magnitude of physical activity that induces anginal chest pain.

Nocturnal angina is the occurrence of anginal discomfort either during the first hours of sleep or during the early morning hours. It is speculated that discomfort caused during the first hours of sleep is due to increased venous return, whereas the discomfort caused during the early morning hours is due to increased vascular tone.

Postprandial angina pectoris is anginal chest discomfort that occurs following meals. It is thought to be due to an increase in vascular tone or a reduction in coronary blood flow.

Cardiac syndrome X is angina associated with objective evidence of myocardial ischemia in the absence of epicardial coronary artery disease. Syndrome X has been hypothesized to be a disorder of the coronary microvasculature rather than the large caliber epicardial coronary arteries.

Coronary vasospasm is a multi-factorial, transient, and abrupt reduction of luminal diameter of an epicardial coronary artery due to inappropriate constriction of coronary smooth muscle that can generate distal ischemia. This may occur spontaneously or in the context of angioplasty, particularly if denudation of the endothelium or dissection occurs. In addition, the vasospasm can either be focal or multifocal (which compromises more than one vessel).

Stable angina must be differentiated from unstable angina and acute coronary syndromes. If the pattern of angina is stable, this is termed chronic stable angina. If the magnitude, threshold or frequency of chest pain accelerates, this is termed an acute coronary syndrome.

The primary causes of myocardial ischemia in chronic stable angina are: fixed epicardial stenosis, spasm of the epicardial artery and/or microvascualar disease. The causation of angina is not mutually exclusive. Two or more causes may coexist in the same patient.

Coronary artery disease (CAD) remains the single leading cause of death in the United States. Stable angina is the initial manifestation of ischemic heart disease in approximately 50% of these patients.

The average mortality in patients with stable angina ranges from 1-3%. However, the prognosis varies widely depending on various factors such as: the duration and severity of symptoms, resting ECG abnormalities, abnormal left ventricular function and associated comorbidities.^[2]

Pretest probability is defined as the probability of the target disorder before the result of a diagnostic test is known. A number of studies have emphasized the importance of pretest probability of coronary artery disease (CAD).^[3] Once a thorough patient history and physical examination is complete, it is important to assess the probability of underlying CAD, as this helps both the physician and the patient to determine the next step in the diagnosis and treatment. In patients with chronic stable angina, the strongest predictors contributing to underlying significant CAD include: the age, gender and type of pain (typical, atypical) experienced.^[3]

Ischemic heart disease remains as the number one cause of mortality in developed countries. The prognosis of stable angina varies widely depending on severity of symptoms, extent of atherosclerosis and presence of other risk factors and co-morbidities. The presence of impaired left ventricular function is associated with a poor prognosis. Reduced LV function, number and location of stenoses, workload in METs calculated using Duke score are the strongest predictors of survival in patients with chronic stable angina.

The name ‘angina pain’ can be thought of as a misnomer as patients often describe the sensation as discomfort rather than physical pain. The best method to characterize this discomfort/pain is through the ‘PQRST system’.

Among patients with chronic stable angina, the physical examination may be asymptomatic or characteristically normal. Patients that present with left ventricular dysfunction are associated with a poorer prognosis than patients who do not present with dysfunction. All patients should be examined carefully for the presence of rales and other signs of heart failure. The majority of patients present with history of either, chest pain or discomfort categorized as: typical or atypical. Typical presentation would include pain or discomfort in the front or anterior precordium. Atypical presentation can be more convoluted in presentation and involve a wide range of symptoms. For example, an atypical patient may present with dyspnea instead of chest pain and this is termed an angina equivalent. In addition to the historical presentation of chest pain or discomfort, the patient history should be extensively evaluated to include an assessment of cardiovascular risk factors. Physical examination may be normal or asymptomatic. In some cases, a physical examination may reveal heart failure. Additional findings can be important in understanding the onset of the condition. For instance, the presence of peripheral vascular disease may be associated with an increased risk of coronary artery disease (CAD).

Criteria for test selection hinges largely on the current disease state of the individual patient and subsequent level of fitness for testing. Potential diagnostic testing modalities include: exercise ECG, ECG at rest, exercise echocardiography, echocardiography at rest, and stress scintigraphy.

In patients with chronic stable angina, initial laboratory investigations are used to: identify potential causes of ischemia, establish risk factors, and determine the overall prognosis for the patient. An initial laboratory test can provide a wide variety of clinical information. For instance, low hemoglobin levels can cause ischemia. Therefore, assessing hemoglobin as a part of complete blood count provides prognostic information.^[4] Biomarkers, such as troponin and CK-MB, are used to exclude myocardial injury. In assessment for risk factor stratification, all patients with ischemic heart disease are recommended to have a a standard round of blood work conducted including fasting plasma glucose levels and a complete lipid profile. Serum creatinine^[5] is used to assess renal dysfunction^[6] due to associated hypertension or diabetes and remains a negative prognostic factor. In patients with chronic stable angina, an elevation in fasting glucose^[7] independently predicts the adverse outcome. Recent research on NT-pro-BNP has demonstrated the ability to predict long-term mortality in patients with chronic stable angina independent of age, ventricular ejection fraction and other risk factors.^[8]

A resting 12-lead ECG is performed and recorded in all patients with suspected angina pectoris. However, a normal resting ECG does not exclude the diagnosis of ischemia. Abnormalites commonly observed on resting ECG include: ST-segment changes, left ventricular hypertrophy (LVH), left branch bundle blockage (LBBB), signs of coronary artery disease (CAD) such as previous myocardial infarction (MI) or abnormal repolarization patterns.^[9] An ECG recorded during pain helps to identify an underlying vasospasm.

In patients with chronic stable angina, exercise ECG is more sensitive and specific to identify inducible ischemia and to diagnose coronary artery disease.^[10] ECG abnormalities associated with MI include: down sloping of ST-segment depression or elevation, accompanying angina that occurs at a low workload during early stages of exercise and persistent for more than 3-minutes after exercise. The reliability of diagnosis is shown to improve with the evaluation of ST changes in relation to heart rate.^[11] Bruce protocol or treadmill (expressed in terms of METs) or bicycle ergometer (expressed in terms of watts) are used to detect MI. Exercise ECG test must be terminated on the achievement of maximal predicted heart rate and/or if the patient becomes symptomatic or develops pain with significant ST-segment changes. Exercise ECG test also provides prognostic stratification to evaluate the response to medical therapy or revascularization.^[12]

Routine chest x-ray examination is important in the evaluation of patients with signs or symptoms of congestive heart failure,^[13] valvular heart disease, pericardial disease, or aortic dissection/aneurysm. The presentation of cardiomegaly, characterized by pulmonary congestion on a chest x-ray, is indicative of a poor prognosis for the patient.^[14]

Pharmacologic stress testing using myocardial perfusion scintigraphy or echocardiography can be employed in patients with known or suspected angina pectoris who are unable to perform adequate exercise tests. These patients often owe their ineligibility status to associated conditions such as: peripheral vascular disease, musculoskeletal disorders, diseases of the lower extremities, severe obesity, or deconditioning. Pharmacologic stress testing is achieved with the infusion of either dobutamine in incremental dose, which acts by increasing myocardial oxygen consumption and thereby mimic effect of exercise, or with the use of coronary vasodilators such as adenosine or dipyridamole, which acts by differentiating regions based on perfusion. Stress imaging is of great value in the evaluation of patients with low pretest probability of CAD.^[15] However, in patients with LBBB, perfusion scintigraphy is shown to have poor diagnostic accuracy.^[16]

In patients with baseline ECG abnormalities,a myocardial perfusion test can be used to localize the region of ischemia. Thallium-201 and technetium-99m are the two radio-labeled agents that are frequently used for the assessment of myocardial perfusion. Myocardial uptake of thallium-201 chloride is directly proportional to the regional myocardial blood flow and is dependent on the presence of viable myocardium. In patients with known CAD, a normal thallium stress test without a perfusion defect is indicative of a benign process and associated with excellent prognosis. Patients with a normal thallium scan are at low risk for CAD and subsequent coronary angiography is indicated only if the patient has a high probabilty Duke treadmill score. Contraindications for thallium stress test include the presence of arrhythmia, acute myocarditis, severe aortic stenosis and acute MI within the past 2 days.

Echocardiography is useful to evaluate ventricular function^[17] and detect ischemia induced regional wall motion abnormality that occurs at rest, during exercise or with pharmacologic stress test. As a testing modality, two-dimensional echocardiography is often coupled with other testing modalities to detect regional wall motion abnormalities that most frequently occur during induced myocardial ischemia associated with coronary artery disease (CAD). Potential paired testing modalities include: upright treadmill exercise, supine bicycle ergometry, pacing, and pharmacologic stress, particularly with dobutamine. Patients with CAD may respond more adversely to testing modalities than their counterparts. Often, an adverse outcome such as the inability to perform a bicycle ergometry test or exercise treadmill protocol can be characterized as a poor prognostic factor.

Stress echocardiography is echocardiography that is paired with different forms of stressors, such as exercise or pharmacological. Exercise stress echocardiography is the preferred stress echocardiography modality. However, it is not suitable for all patients and may not be feasible in populations that do not meet a minimum level of fitness. In patients who are ineligible for exercise stress echocardiography, pharmacological stress echocardiography can be a useful alternative. Common pharmacological stressors include: adenosine, dipyridamole, and dobutamine. As a testing modality, exercise echocardiography is noted as more sensitive, more specific and has a higher predictive value than exercise ECG. Exercise echocardiography can be helpful in the evaluation of regional wall motion response, location and extent of ischemia during stress in patients with MI. During exercise, the normal myocardium is hyperdynamic while in patients with MI, the ischemic myocardium is either akinetic or hypokinetic.

Positron emission tomography is of particular value in the assessment of regional coronary blood flow reserve, myocardial perfusion, and the presence and extent of hibernating myocardium.

Ambulatory ECG monitoring (Holter monitor) is used to detect major arrhythmias and myocardial ischemia occurring during normal activities. Ambulatory ECG monitoring adds very little prognostic value in patients with chronic stable angina, however, does play a role in the detection of major arrhythmias in patients with chronic stable angina and suspected vasospastic angina.

The extent of coronary artery calcification directly correlates to the area of atheromatous plaque.^[18] Hence in patients with chest pain, coronary artery calcium (CAC) scoring is one of the factor to be considered in the risk assessment for coronary artery disease. The methods used for detection and quantification of CAC include electron beam computed tomography (EBCT) and multi-detector computed tomography (MDCT).^[19] Agatston score is a computed software that is commonly used to measure CAC based on the density and area of calcified plaques.^[20]

Cardiac magnetic resonance imaging (CMRI) is a non-invasive test that is useful in the evaluation of overall coronary anatomy and function. CMRI also helps in the identification of inflammation,^[21] neovascularization^[22] and fibrous cap.^[23] It, therefore, holds the potential for plaque characterization.

Coronary angiography is a gold standard test in the evaluation of severity of coronary artery disease and the possibility for revascularization. Coronary angiography is indicated in patients with a high pretest probability of CAD and in symptomatic patients with inconclusive initial noninvasive tests. Provocative testing with ergonovine during angiography may be useful in patients with vasospastic angina. Major complications such as death, MI and stroke associated with routine angiography is as low as 0.1% – 0.2%.^[24]

Treatment of chronic coronary disease/chronic coronary syndromes aims to minimize symptoms and improve quality of life, and to reduce cardiovascular events through guideline-directed secondary prevention therapies.^[25][26] Treatment includes lifestyle modification, event-preventing GDMT (antithrombotic therapy, intensive lipid lowering, BP/diabetes therapies, and selected cardiometabolic agents), antianginal drugs for symptom control, and revascularization when indicated.^[25][26]

Initial management is GDMT, with revascularization considered for

(1) unacceptable angina/ischemia despite optimized medical therapy, and/or

(2) selected patients with high-risk anatomy/physiology where revascularization may reduce spontaneous MI and cardiovascular death during long-term follow-up.

The choice of PCI versus CABG should be individualized using a Heart Team approach based on coronary anatomy/complexity (including left main and multivessel disease), LV function, diabetes, bleeding/ischemic risk, and likelihood of complete revascularization.^[25][26]

Pharmacotherapy includes (a) antianginal therapy for symptom relief and (b) secondary-prevention GDMT to reduce cardiovascular events.^[27][28] Mainstays include patient education, lifestyle changes, and GDMT. For angina relief, either a beta-blocker or a calcium-channel blocker is recommended as first-line therapy; long-acting nitrates and other agents may be added if symptoms persist or first-line therapy is not tolerated^[27][28] In patients with chronic stable angina, immediate symptomatic relief is achieved with short-acting sublingual nitrates and long term symptom relief is achieved with beta blockers as first line therapy, or calcium channel blockers and long-acting nitrates when beta blockers are contraindicated. Event-preventing therapies include antiplatelet therapy and intensive lipid lowering for most patients; ACEi/ARB is recommended when indicated (e.g., hypertension, diabetes, CKD, or LV systolic dysfunction). Long-term beta-blocker therapy is not recommended solely to improve outcomes in CCD in the absence of MI within the past year, LVEF ≤50%, or another primary indication.^[27][29]

In patients with ischemic heart disease, prophylactic low dose aspirin A single antiplatelet agent (aspirin or clopidogrel) is generally recommended long term in CCS patients with obstructive atherosclerotic CAD, with choice individualized to ischemic and bleeding risk.^[28]

Dipyridamole is a pyrimidopyrimidine derivative with poor anti-thrombotic efficacy and therefore not recommended for anti-platelet therapy in patients with chronic stable angina.^[30] Dipyridamole may also exacerbate anginal symptoms due to coronary steal phenomenon.^[31]

Thienopyridines, such as clopidogrel and ticlopidine, selectively inhibit ADP-induced platelet aggregation and are used as an alternative to aspirin in patients with significant risk of arterial thrombosis.

Short-acting nitrates provide rapid symptom relief and can be used for situational prophylaxis; long-acting nitrates are used for ongoing symptom control as add-on therapy when first-line agents are insufficient or not tolerated.^[27][28] Organic nitrates are therapeutic precursors of endothelium-derived relaxing factor that produce their beneficial effects both, by decreasing myocardial oxygen requirements and by improving myocardial perfusion. The most commonly used nitrates are nitroglycerin, isosorbide dinitrate and isosorbide mononitrate. Short acting nitrates, such as sublingual nitroglycerin, are best suited to treat acute episodes of angina and are effective when used for situational prophylaxis. Long-acting nitrates help to reduce the frequency and severity of angina and may increase exercise tolerance in patients with stable angina.^[32][33][34] Nitrates at therapeutic doses do not affect coronary vascular resistance, consistent with the use of dipyridamole and other short acting dihydropyridines.

In patients with stable angina, beta blockers are used as a first line of therapy for both, symptomatic relief^[35][36][37] Beta-blockers are effective for symptom relief; long-term beta-blocker therapy is not recommended to improve outcomes in CCD in the absence of MI in the past year, LVEF ≤50%, or another primary indication (e.g., arrhythmia or uncontrolled hypertension).^[27][38] The physiologic mechanism of benefit of this therapy is a marked reduction in myocardial oxygen consumption by reducing the heart rate and myocardial contractility. Selective beta-1 blockers are preferred to non-selective beta-blockers due to fewer associated side effects.^[34] When LV systolic dysfunction is present (LVEF <50%), use evidence-based beta-blockers (metoprolol succinate, carvedilol, or bisoprolol) in preference to other beta-blockers.^[29]In patients started on beta-blockers after MI who have no current LVEF ≤50%, angina, arrhythmia, or uncontrolled hypertension, reassessment of the need for therapy beyond 1 year may be reasonable.^[29]

Calcium-channel blockers are first-line antianginal therapy (alternative to beta-blockers) and are particularly useful for vasospastic angina.^[27][28]Avoid verapamil and diltiazem in HFrEF due to increased heart-failure events. The beneficial anti-anginal effects of CCB include: reduction in the afterload consequent to systemic vasodilation as well as epicardial vessel vasodilation, enhancement of the coronary collateral flow with subsequent sub-endocardial perfusion due to the inhibition of calcium influx via L-type channels.^[39] Long-acting calcium channel blockers are an effective antianginal agent and are considered to be the first choice in post-MI patients with a contraindication to beta-blocker.^[40] Long-acting CCBs are also specifically used to control symptoms in patients with vasospastic angina.^[41] However short-acting CCBs, such as nifedipine, are avoided due to an increased risk of myocardial infarction and mortality.^[42][36][37]

Nicorandil has both, anti-anginal effects due to nitrate-like and ATP-sensitive potassium channel activating properties and nicorandil can be used as add-on/alternative antianginal therapy when beta-blockers/CCBs are insufficient or not tolerated (availability varies by country).^[28] Therefore, nicorandil usage in addition to standard anti-anginal therapy may be indicated in patients who are intolerant to beta-blocker therapy or in whom CCB monotherapy or combination therapy CCB is unsuccessful.^[43][44][45].

Ranolazine is a one of the newer FDA approved anti-anginal medication for management of chronic stable angina. Perhexiline is another anti-anginal, primarily used in Australia and New Zealand, being studied for use in the United States and UK. In patients with chronic stable angina, other effective agents with anti-anginal and anti-ischemic properties are ivabradine, trimetazidine and molsidomine.Antianginal drugs are primarily for symptom relief and generally do not reduce MACE; selection and combination should be individualized to haemodynamics (HR/BP), comorbidities, and tolerability.Ivabradine should not be combined with verapamil or diltiazem and is mainly considered in selected patients with LV systolic dysfunction.^[28]

ACE inhibitor/ARB therapy is recommended in CCD when indicated (e.g., hypertension, diabetes, CKD, or LV systolic dysfunction) as part of event-preventing GDMT.^[46][47][48] Based on the recent AHA and ESC guidelines, the recommended goal blood pressure in patients with atherosclerotic coronary vascular disease is less than 130/80 mm Hg.^[49][45][50]

Statins by inhibiting HMG-CoA reductase subsequently reduce serum cholesterol levels and have been shown to be effective in the primary prevention of various hyperlipidemias and secondary prevention of ischemic heart disease.^[51][52] The most commonly used statins are simvastatin, atorvastatin, pravastatin and rosuvastatin.Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.] Lancet 361 (9364):1149-58. DOI:10.1016/S0140-6736(03)12948-0 PMID: 12686036</ref>^[53]Statins are first-line lipid-lowering therapy in CCD/CCS; adjunctive agents (ezetimibe, PCSK9 inhibitors, bempedoic acid, and inclisiran) may be used in select populations to further lower LDL-C, noting that clinical outcomes data are unavailable for some newer agents such as inclisiran. ^[27]

The goal of the treatment of chronic stable angina is to reduce the symptoms, delay the progression of atherosclerosis, and prevent cardiovascular events. In order to achieve these goals, lifestyle modifications and medical therapy are the first line treatment. Revascularization is done to increase survival in specific conditions where the stenosis of the coronary arteries is anatomically and functionally significant and the symptoms are refractory to medical therapy. There are currently two well-established revascularization approaches for the treatment of chronic stable angina caused by coronary atherosclerosis: CABG and PCI. Since the introduction of coronary artery bypass surgery in 1967 and percutaneous transluminal coronary angioplasty (PTCA) in 1977, research has supported the effective usage of both strategies for treatment of patients with chronic stable angina. However, as with any treatment method, both methodologies have weaknesses. The choice between PCI and CABG is based upon anatomy and other factors such as left ventricular function and the presence or absence of diabetes. Selection of PCI vs CABG should be individualized using a Heart Team approach based on coronary anatomy and complexity (including left main and multivessel disease), diabetes, LV function, and feasibility of complete revascularization.^[54][28]When invasive angiography is performed, invasive functional assessment (FFR/iFR) is recommended for intermediate stenoses to guide revascularization decisions.

Percutaneous coronary intervention (PCI) is performed to relieve angina/ischemia and, in selected higher-risk obstructive CAD, to reduce long-term spontaneous MI and cardiac death.^[27][28]For angiographically intermediate stenoses, invasive physiology with FFR or iFR is recommended to guide PCI decisions; PCI should not be performed when FFR is >0.80 or iFR is >0.89 because outcomes with medical therapy alone are favorable.^[54]Revascularization generally provides greater improvement in angina and quality of life than medical therapy alone, and placebo-controlled data confirm angina relief from PCI in patients with stable angina and ischemia.

Coronary artery bypass grafting (CABG) is preferred for prognosis in significant left main disease and for many patients with complex multivessel CAD, particularly when complete revascularization by PCI is unlikely; Heart Team selection is recommended when the optimal strategy is unclear.^[27][54]

An increased risk of mortality and morbidity is associated with untreated coronary artery disease.^[55] The main aim of therapy in patients with chronic stable angina is to alleviate symptoms, delay the progression of atherosclerosis, reduce the incidence of adverse coronary events and improve prognosis. This may be achieved with either initial medical therapy or with initial revascularization that includes percutaneous coronary intervention or coronary artery bypass grafting. Medical therapy alleviates symptom and improves prognosis; however, on the contrary, PCI improves angina and quality of life, while effects on survival are nuanced and depend on anatomy, ischemic burden, LV function, and comorbidities; overall, many CCD trials show no all-cause mortality reduction with routine revascularization, with important exceptions (e.g., CABG in left main disease and in severe LV dysfunction).^[27][28][54]In FAME 2 (NEJM RCT; 888 randomized), FFR-guided PCI vs medical therapy reduced the composite of death/MI/urgent revascularization at 5 years (13.9% vs 27.0%, HR 0.46, P<0.001), driven mainly by fewer urgent revascularizations (6.3% vs 21.1%, HR 0.27) with no significant difference in death (5.1% vs 5.2%) and a borderline MI reduction (8.1% vs 12.0%, HR 0.66, 95% CI 0.43–1.00.^[56]At median 11.2 years in long-term follow-up (748 randomized with extended follow-up), FFR-guided PCI reduced the composite hierarchical endpoint (33.6% vs 41.3%; win ratio 1.25, 95% CI 1.01–1.56, P=0.043) with no all-cause death difference (win ratio 0.88, 95% CI 0.66–1.17).^[57]

CABG improves survival compared with medical therapy in significant left main disease and in selected patients with CCD and severe LV dysfunction (especially LVEF ≤35%); benefits are less consistent in patients with normal LV function and without left main/proximal LAD high-risk anatomy.^[27][54][58] However, the long term benefit of CABG is limited by the progression of atherosclerosis in other unbypassed vessels and stenosis of the graft itself.

Older revascularization trials predate contemporary GDMT and contemporary stent/physiology-guided strategies; current decisions should be guided by anatomy/complexity, ischemia/physiology, symptoms on optimized GDMT, and Heart Team discussion.^{[27][28][59][60]} However, there are a few reservations to the application of results from these studies as they did not include the current optimal strategies of therapy.

PCI and CABG have become the standard of care in the management of patients with symptomatic coronary artery disease. Patients with multi-vessel disease^[28][54], PCI vs CABG choice depends on anatomic complexity, diabetes, LV function, and completeness of revascularization; Heart Team evaluation is recommended when strategy is unclear

As the survival of patients with primary coronary events continue to increase, the number of patients presenting with refractory ischemia despite maximal medical therapy and unsuitable for further traditional revascularization techniques also continues to rise.^[61] Transmyocardial revascularization (TMR) is one of the emerging techniques that has been studied in many randomized trials and has shown to reduce the incidence of recurrent angina, increase exercise tolerance time and improve quality of life.^[61][62] TMR can be performed using either a laser beam or a percutaneous approach. However, only laser TMR is currently FDA approved.

In patients with refractory angina, spinal cord stimulation (SCS) is used to provide analgesia in the region of radiation of anginal-pain with the help an implanted device consisting of a stimulating electrode tip that extends into the dorsal epidural space, usually at the C7-T1 level.

Enhanced external counter pulsation (EECP) is another alternative therapy in the management of refractory angina. Most data from observational studies have demonstrated significant improvement in the exercise tolerance and reduction in the frequency of anginal symptoms as well as the use of nitroglycerin among patients treated with EECP.^[63]

Ongoing follow-up of the patient with chronic stable angina is necessary to monitor symptoms and to optimize antianginal therapy. It is generally recommended that these patients be evaluated every 4-6 months during first year of diagnosis/initiation of therapy and annually thereafter. Based upon clinical judgement, if the patient is poorly responsive to therapy, if the episodes are severe or frequent, or if the patient is fragile with multiple co-morbidities, they may need to be seen more frequently.

During a follow-up visit, the patient should be asked about the frequency and severity of their anginal symptoms, their level of exercise capacity, whether they have been able to modify his/her risk factors, how well they are tolerating and complying with the therapy and whether he/she has developed new illnesses or co-morbidities.Routine functional testing is not recommended for asymptomatic post‑PCI patients.^[28]

Cardiac rehabilitation (CR) is a comprehensive outpatient secondary-prevention intervention combining supervised exercise training, education, risk-factor management, psychosocial support, and medication optimization to improve functional capacity and quality of life and reduce morbidity and cardiovascular mortality.^[64][65]CR should be prescribed for eligible patients with chronic coronary disease, including those with stable angina and those after MI, PCI, or CABG, ideally before discharge or at the first outpatient visit.^[66]Home-based CR is a reasonable alternative to center-based CR for clinically stable patients who cannot attend in-person programs, with similar short-term improvements in functional status and quality of life.^[67][68] The main goal of rehabilitation is to help patients understand their disease and inculcate a regimen to stabilize and reduce, or even reverse the progression of cardiovascular disease. Cardiac rehab is often divided into phases that involve monitored exercise, counseling, emotional support, and education about lifestyle changes to reduce the risks of heart problems. It also helps reverse limitations experienced by patients who have suffered the adverse patho-physiologic and psychological consequences of cardiac events, thus, also helping patients to return to work early. Eligibility and exercise prescription should be individualized using baseline clinical assessment and exercise testing when feasible.^[69] However, rapid evolution in the management of CAD has now changed the demographics of the patients, so that, even patients with recent revascularization can be candidates for rehabilitation training.

The 1989 Surgeon General’s report, which assessed numerous case-control and cohort studies, reported that smoking increased cardiovascular disease mortality by 50%.^[70] Cigarette smoking, likely due to the hemodynamic consequences of sympathetic neural stimulation and systemic catecholamine release, plays an important role in the pathogenesis of coronary artery disease. Cigarette smoking also forms a major risk factor for acute cardiovascular events as it relates to an associated increase in blood coagulability.^[71] Hence, cigarette smoking is an important reversible risk factor in the pathogenesis of CAD and cessation of which improves prognosis and is associated with a substantial decrease in the risk of mortality.^[72][73][74] In patients with stable angina pectoris, nicotine replacement therapy has shown to be potentially beneficial despite the associated cardiovascular risks of nicotine, such as increase in heart rate with a small rise in blood pressure. Pharmacotherapy for tobacco cessation (including nicotine replacement) should be individualized based on clinical stability and comorbidities.^[27][71] Additionally, nicotine patches have been used successfully in high-risk patients without any adverse effects such as aggravation of MI or arrhythmia.^[75][76]

Obesity is directly associated with the development of coronary artery disease (CAD) risk factors such as: hypertension, diabetes, reduced levels of HDL-C and elevated levels of triglyceride. Research has demonstrated that CAD risk factors contribute to a strong, graded, J-shaped univariable relationship between BMI and cardiovascular disease mortality. This increased mortality, when adjusted for age, self-reported smoking status, total cholesterol, and systolic blood pressure, maintained significant hazard ratios.^[77] Hence, in obese patients with CAD, weight reduction and/or dietary interventions may be warranted to reduce the incidence of above-mentioned risk factors and prevent future coronary events. Weight reduction is strongly recommended in patients with a BMI greater than 30 kg/m² and in patients with increased waist circumference (greater than 102 cms for men and 89 cms for women), characteristic of truncal obesity.^[49] Based on the plasma lipid abnormalities, adequate dietary modification may also be indicated.^[78]

Based on an individual’s ability to exercise and severity of the symptoms, physical activity may be indicated as a treatment. As a treatment, increased physical activity has demonstrated improvements in an individual’s sustained exercise duration, reduced the frequency of symptoms and also provided beneficial effects on blood pressure, diabetes and the overall lipid profile. For CCD patients without contraindications, an exercise regimen is recommended, targeting ≥150 minutes/week moderate-intensity aerobic activity or ≥75 minutes/week vigorous aerobic activity (or equivalent), plus resistance training on ≥2 days/week; intensity should be individualized and may be guided by exercise testing when available.^[27][28][79]Exercise is contraindicated in unstable/refractory angina, decompensated heart failure, high-grade arrhythmias, active thromboembolic disease, or other unstable severe noncardiac illness.

In patients with established coronary artery disease, in ESC CCS guidance, LDL-C goal for very-high-risk ASCVD is <55 mg/dL (<1.4 mmol/L) and ≥50% reduction from baseline; consider <40 mg/dL (<1.0 mmol/L) for recurrent vascular events within 2 years on maximal therapy.^[28][49] In patients with CAD, a fasting lipid-profile may be repeated at 5 year intervals to assess the overall risk of cardiovascular mortality and morbidity.^[80] Based on the individual’s lipid abnormalities, necessary dietary interventions and/or lipid-lowering agents are suggested to prevent the risk of future coronary events.^[78] A Mediterranean diet consisting of fruits, vegetables, lean meat and fish has also been shown to be beneficial. Nonprescription or dietary supplements (including fish oil/omega‑3 fatty acids and vitamins) are not recommended for reducing cardiovascular events in CCD.^{[27][81][82][83][84]} Fish consumption once a week has also been associated with reduced risk of mortality from coronary artery disease and, for this reason, is strongly recommended.^[85][86]

The risk of progression of atherosclerosis is proportional to the increase in elevated blood pressure, hyperglycemia and dyslipidemia. Therefore, the control of hypertension, hyperglycemia and other features of metabolic syndrome deserves special attention in the prevention of mortality and morbidity due to coronary artery disease. In patients with established CAD, concomitant diabetes and/or renal dysfunction, blood pressure control to <130/<80 mm Hg is a CCD performance-measure target; therapy should be individualized to overall risk and tolerability.^[46][80][87] Close monitoring and lifestyle changes may be indicated in low-risk patients without documented target organ damage. However, in high-risk patients with a sustained SBP of ≥140 mm Hg and/or DBP ≥90 mm Hg, the goal is to lower blood pressure less than 140/90 with the help of combined drug therapy and life style modification. Anti-hypertensive therapies that have shown to significantly reduce cardiovascular mortality and morbidity in patients with coronary artery disease include diuretics, beta-blockers, ACEIs, ARBs and calcium channel blockers.

Diabetes is one of the major modifiable risk factors for coronary artery disease. Maintaining a good glycemic control has been demonstrated to delay the disease progression in patients with impaired glycemic control and further prevent microvascular complications.^[87][88][89] In type 1 diabetics, appropriate insulin therapy and concomitant dietary modification may be required. However, in patients with type 2 diabetes, a multi-factorial intervention involving increased physical activity, weight reduction, dietary modification and/or drug therapy in CCD with type 2 diabetes, use of SGLT2 inhibitors and/or GLP‑1 receptor agonists with proven cardiovascular benefit is recommended for select groups, including some patients without diabetes depending on indication.^[46][80][90]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

The primary causes of myocardial ischemia in chronic stable angina are: fixed epicardial stenosis, spasm of the epicardial artery and/or microvascualar disease. The causation of angina is not mutually exclusive. Two or more causes may coexist in the same patient.

The primary causes of myocardial ischemia in chronic stable angina are explained below:

1. Fixed epicardial stenosis: Most commonly, chronic stable angina is the result of fixed obstructive disease or atherosclerosis that causes narrowing of the coronary arteries.

• This results in inadequate supply of blood and oxygen to meet the demands of myocardial metabolism. This supply/demand mismatch activates a molecular cascade of events that causes the release of molecules, such as bradykinin and adenosine, which in turn stimulate the sympathetic and vagal afferent fibers, causing the anginal pain.
• Certain conditions can increase the myocardial oxygen demand secondary to an increase in cardiac output and can exacerbate chronic stable angina. These conditions include, but are not limited to:

• Fever
• Thyrotoxicosis
• Anemia
• Emotional stress
• Tachyarrythmias

The increase in cardiac demand is often treated with beta blockers as a method to treat the underlying condition.

2. Spasm of the epicardial artery: While fixed obstructive epicardial disease is the most common cause of chronic stable angina, vasospasm of the epicardial artery can also cause angina. Angina due to spasm of an epicardial artery is known as prinzmetal’s angina or variant angina. Prinzmetal’s angina or variant angina is often treated with calcium channel blockers to relieve the spasm.

3. Microvascular disease: Chronic stable angina can also result from microvascular disease as well. This is known as microvascular angina or syndrome X. Microvascular angina is often treated with calcium channel blockers to relieve the spasm.

Angina that is precipitated by an increased myocardial oxygen requirement is sometimes referred to as demand angina or fixed threshold angina. In demand angina, evidence of increased cardiac oxygen requirements can be suspected in the following situations:

• The factors mentioned below may trigger the release of norepinephrine, which increases myocardial oxygen requirements:

• Physiological responses to physical exertion, mental, or emotional stresses
• In the presence of fever, hypoglycemia, and conditions like sustained tachyarrhythmias, signs of hyperthyroidism and thyrotoxicosis
• Distinctly elevated blood pressure such as during a hypertensive crisis

• Another cause of increased myocardial oxygen demand is an arteriovenous fistula (AVF) in patients receiving dialysis.
• Acute exacerbation of chronic obstructive pulmonary disease (COPD) (with or without superimposed infection) can dramatically lower oxygen saturation levels and aggravate ischemia related symptoms in patients with coronary artery disease.

Demand angina has few dynamic (i.e. vasoconstrictor effect) components, and the amount of physical activity required to precipitate angina remains relatively constant.

• Angina that occurs secondary to a decrease in oxygen supply is sometimes referred to as supply angina or variable threshold angina.
• Major determinants of myocardial oxygen consumption are:

• Ventricular wall tension: intraventricular systolic pressure, ventricular volume, and ventricular wall thickness are the major determinants of left ventricular wall tension.
• Heart rate: Various forms of tachycardias and tachyarryhthmias may also increase myocardial oxygen consumption and reduce myocardial perfusion by decreasing the duration of diastole. Therefore, reduction of heart rate is associated with a decrease in myocardial oxygen demand and improved left ventricular perfusion.
• Myocardial contractility: adrenergic stimulation of the heart and tachycardia serve as major determinants of contractility.

• Myocardial oxygen extraction is almost at maximal level at rest and arterial oxygen content is usually stable. However, anemic or marked hypoxic states are an exception. Therefore, myocardial oxygen supply is mainly determined by coronary blood flow.
• Coronary blood flow is a function of myocardial perfusion pressure (the difference between the diastolic pressure in aortic root and the right atrium). The duration of diastole has an inverse relation with the coronary vascular resistance. Coronary vascular resistance, in turn, is determined by:

• The severity of epicardial coronary artery stenosis
• The changes in epicardial coronary artery tone
• Coronary arteriolar resistance, which is regulated by metabolic, neural, humoral, and autonomic activity.

• Myocardial demand for oxygen increases during exertion. In physiologically normal persons, increased myocardial oxygen demand during exercise reduces coronary arteriolar resistance, resulting in an increase in coronary blood flow (called an autoregulatory reserve). This autoregulatory reserve progressively diminishes with an increased severity of epicardial coronary artery stenosis. When coronary artery stenosis reaches 90% of the luminal diameter, dilatation in coronary arteriolar bed approaches its maximum level and coronary blood flow becomes more dependent on perfusion pressure. Under these conditions, reduction of arterial pressure may increase in myocardial oxygen demand and induce myocardial ischemia.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Vijay Kunadian, M.D., Ph.D.; Smita Kohli, M.D.; Lakshmi Gopalakrishnan, M.B.B.S., Aysha Aslam, M.B.B.S[3]

Synonyms and keywords: Stenocardia; angina pectoris; angor pectoris

Classic: Chronic Stable Angina

Atypical: Walk through Angina | Mixed Angina | Nocturnal Angina | Postprandial Angina | Cardiac Syndrome X | Vasospastic Angina

ECG/Chest X-Ray | Rest LV Function | Exercise Treadmill Test | Stress Imaging in Patients who are Able to Exercise | Stress Imaging in Patients who are Unable to Exercise | Coronary Angiography

History and Symptoms | Physical Examination | Test Selection Guideline for the Individual Basis | Laboratory Findings | Electrocardiography | Exercise ECG | Chest X-Ray | Myocardial Perfusion Scintigraphy with Pharmacologic Stress | Myocardial Perfusion Scintigraphy with Thallium | Echocardiography | Exercise Echocardiography | Positron Emission Tomography | Ambulatory ST Segment Monitoring | Electron Beam Tomography | Cardiac Magnetic Resonance Imaging | Coronary Angiography

Medical Therapy:

Anti-platelet Agents: Aspirin | Dipyridamole | Clopidogrel

Anti-anginal Agents: Nitrates | Beta Blockers | Calcium Channel Blockers | Potassium Channel Openers | Newer Anti-anginal Agents

ACEI/RAAS Blockers

Anti-lipid Agents

Guidelines for Pharmacotherapy

Revascularization: PCI | CABG | Guidelines for Revascularization | PCI vs Medical Therapy | CABG vs Medical Therapy | PCI and CABG versus Medical Therapy | PCI vs CABG

Alternative Therapies for Refractory Angina: Transmyocardial Revascularization (TMR) | Spinal Cord Stimulation (SCS) | Enhanced External Counter Pulsation (EECP) | ACC/AHA Guidelines for Alternative Therapies in patients with Refractory Angina

Patient Follow-Up | Rehabilitation

Overview | Smoking Cessation | Weight Management | Physical Activity | Lipid Management | BP Control | Diabetes Control | Influenza Vaccination | ACC/AHA Guidelines for Cardiovascular Risk Factor Reduction

Noninvasive Testing in Asymptomatic Patients | Coronary Angiography in Asymptomatic Patients | Pharmacotherapy to Prevent MI and Death in Asymptomatic Patients

Case #1

• Exercise stress testing
• Exercise Tolerance Test Time as an Endpoint for Clinical Trials Evaluating Therapies for Refractory Angina
• For other uses of the term angina: Unstable angina, Abdominal angina, Ludwig’s angina, Prinzmetal’s angina, Vincent’s angina, or Angina tonsillaris

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