ANGINA PECTORIS

ANGINA PECTORIS

  1. 1
    Current Diagnosis

    • The clinical diagnosis of angina depends largely on the accurate assessment of a patient’s risk factor profile for coronary artery disease and the typicality of the symptom complex.

    • The most common symptom of angina pectoris is left-sided chest pain or pressure, with or without associated radiation of pain or pressure to the jaw or left arm, occurring with exertion and relieved with rest or sublingual nitroglycerin.

    • Women may present with atypical symptoms such as sharp, nonexertional chest pain; generalized fatigue; or right-sided chest pain.

    • Basic screening tests (e.g., 12-lead electrocardiogram, laboratory data, chest radiograph) are normal in most cases.

    • For an initial diagnosis, appropriate noninvasive testing or coronary angiography, or both, is important to define the amount of ischemic myocardium and an overall treatment plan.

    • Even when invasive procedures are clinically indicated, aggressive medical therapy with high-dose statins, attainment of appropriate blood pressure levels, smoking cessation, and use of antiplatelet therapy is of paramount importance.

    • Patients who have clinical evidence of unstable angina and laboratory evidence of myocardial ischemia most often benefit from early invasive treatment strategies.

  2. 2
    Current Therapy

    Stable Angina Pectoris

    • Treatment includes β-blockers, nitrates, and calcium channel blockers for symptom control.
    •  Consider the addition of ranolazine (Ranexa) if symptoms are not adequately controlled.

    Aggressive Cholesterol Treatment Based on the ACC-AHA Blood Cholesterol Guidelines

    • Blood pressure management
    • Antiplatelet therapy
    • Lifestyle modifications:
      • Smoking cessation
      •  Exercise prescription
      •  Dietary guidelines
      •  Depression assessment

    Unstable Angina

    • With positive biomarkers for myocardial ischemia, consider coronary angiography.
    • With negative biomarkers for myocardial ischemia, consider noninvasive assessment once symptoms are controlled.
    • With a substantial ischemic burden identified, consider coronary angiography.
    • With no or minimal ischemia identified, consider increasing medical therapy.
    • With persistent symptoms, consider other treatment modalities.
    • With persistent symptoms, consider other treatment

    Angina pectoris is defined as cardiac-induced pain that is a direct result of a mismatch between myocardial oxygen supply and demand. The initial presentation of ischemic heart disease is chronic stable angina in approximately 50% of patients; it is estimated that 16.5 million Americans have this diagnosis. Ischemic heart disease is the leading cause of death in the United States.

    Stable angina refers to predictable chest discomfort during various levels of exertional activity that is predictably resolved with rest or administration of sublingual nitroglycerin (Nitrostat). Unstable angina is an acute ischemic event; this diagnosis includes patients with new- onset cardiac chest pain, angina at rest, postmyocardial infarction angina, or an accelerating pattern of previously stable angina. The terms unstable angina and non–Q wave myocardial infarction are often used interchangeably and should be further defined on the basis of myocardial necrosis as measured by serum biomarkers.

    The clinical sensation of angina pectoris is caused by stimulation of chemosensitive and mechanosensitive receptors of unmyelinated nerve cells found within cardiac muscle fibers and around the coronary vessels. This stimulation cascade is thought to occur when lactate, serotonin, bradykinin, histamine, reactive oxygen species, and adenosine are released into the coronary circulation during periods of lactic acidosis. Nerve stimulation via the sympathetic ganglia occurs most commonly between the seventh cervical and fourth thoracic portions of the spinal cord. This explains from an anatomic standpoint why the most commonly recognized pain patterns for angina pectoris involve discomfort in the chest, neck, jaw, and left arm.

    The most common cause of angina pectoris is coronary atherosclerosis. As plaque is initially deposited within a coronary vessel, there may be no significant internal luminal compromise during the early positive remodeling phase. However, at the point at which this compensatory mechanism fails, internal luminal compromise ensues. As long as the coronary artery segment distal to the stenosis retains the ability to vasodilate in response to increasing blood flow demands, coronary homeostasis is maintained. Once the critical threshold is passed, the blood supply cannot accommodate this demand, and angina may occur. The four major factors that determine myocardial oxygen demand are heart rate, systolic blood pressure, myocardial wall tension, and myocardial contractility.

  3. 3
    Clinical Features

    For patients with documented coronary artery disease (CAD) who have predictable episodes of classic symptoms, the diagnosis of angina pectoris is straightforward. Most patients are aware of the levels of exertion that typically induce angina symptoms. Most describe a pain or heaviness across their middle chest that may or may not radiate to the jaw or left arm. Some patients deny chest pain symptoms altogether and instead complain of exertional dyspnea or diaphoresis. Environmental situations such as cold exposure, emotional stress, or heavy meals can induce angina. The Canadian Cardiovascular Society and the New York Heart Association classification systems are used to define angina severity. Both systems use a I through IV scale, with mild angina (class I) referring to episodes that occur with extreme exertion and severe angina (class IV) to episodes that occur with minimal or no exertion. These classification systems are useful for risk stratification and for assessing medical therapy efficacy.

    Table 1

    Differential Diagnosis of Chest Pain

    There are clear gender differences in the clinical presentations of angina. Pleuritic, musculoskeletal-type pain, nonexertional pain, and nocturnal pains have been reported as anginal equivalents in women. Fatigue is one of the most common presenting symptoms for CAD in women. The key to the diagnosis in men and women lies in a thorough history, which should always include the quality, location, provoking activities, and duration of pain and factors that relieve the pain. Based on a detailed clinical history, the many diagnoses that can masquerade as angina may be eliminated (Table 1).

    Cardiac ischemia

    Angina

    Myocardial infarction

    Vasospastic angina

    Pericarditis

    Aortic dissection (new-onset chest pain and new aortic insufficiency noted on auscultation is an aortic dissection until proven otherwise)

    Pulmonary embolism

    Esophageal spasm

    Gastroesophageal reflux disease

    Musculoskeletal pain

    Biliary colic

    Acute pneumonia

  4. 4
    Diagnostic Testing

    A baseline electrocardiogram (ECG) is often one of the initial tests obtained in a patient with the complaint of chest pain. A normal tracing does not exclude the diagnosis of ischemic heart disease. More than 50% of patients with diagnosed angina have a normal ECG at rest. The baseline ECG may, however, show evidence of pathologic Q waves or left ventricular hypertrophy, either of which increases the statistical probability of significant CAD. Baseline laboratory data should include a fasting lipid panel to help define the patient’s risk factor profile.

    Stress testing is an appropriate screening tool for the initial diagnosis of CAD, risk stratification after acute ischemic syndrome, and assessment of treatment efficacy. Whenever feasible, it is more advantageous to obtain an exercise stress test rather than a pharmacologically based study. The additional prognostic data obtained through exercise include blood pressure response, heart rate response, heart rate recovery, metabolic equivalent level attained, and ECG assessment of the ST segment. There are several validated exercise protocols that add additional risk stratification measures to the test results.

    The predictive value of exercise treadmill stress testing ranges from 40% for single-vessel disease to 90% for three-vessel disease. A baseline left bundle branch block, paced rhythm, poorly controlled atrial arrhythmia, or left ventricular hypertrophy with secondary ischemic changes often renders the test inconclusive when assessing for ischemic changes. However, if stress testing is being performed for attainment of hemodynamic responses and achievable metabolic equivalent levels, these baseline ECG abnormalities may be overlooked.

    Stress test accuracy is markedly improved by the addition of an imaging modality such as echocardiography or nuclear perfusion scanning. The sensitivity and specificity of stress echocardiography and stress nuclear imaging are 85% to 90%. Stress echocardiography is believed to be somewhat more specific, and stress nuclear imaging is thought to be more sensitive. A stress echocardiogram also allows assessment of left ventricular systolic function and valvular function and prediction of right ventricular pressure. In deciding on which stress test to perform, one should rely on the expertise of the testing facility and the individual patient’s circumstance.

  5. 5
    Risk Factor Management

    Hypertension

    Hypertension is a commonly occurring, well-established, major cardiovascular risk factor. Initial treatment of hypertension in patients with ischemic heart disease should always include lifestyle management. Appropriate weight loss with a goal of achieving a body mass index < 25 kg/m2 can improve hypertension control. A reduction in dietary salt intake can also have positive effects on a patient’s blood pressure.

    Discord has resulted from the publication of recent hypertension guidelines by various medical societies as well as the 2014 Evidence- Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel Members Appointed to the Eighth Joint National Committee. It has been shown that cardiovascular risk progressively increases at blood pressures greater than 115/75 mm Hg. A meta-analysis of 61 prospective observational trials of hypertension involving 1 million adults with no known vascular disease at baseline revealed several interesting findings. Patient outcomes were related per decade of age to the usual blood pressure at the start of that decade. For example, from ages 40 to 69, for each increase in 20 mm Hg systolic blood pressure, a twofold increase in cardiovascular death rate occurred. These findings were much more pronounced in patients who were between 80 and 89 years old than in the youngest cohort, 40 and 49 years old. Although the relative risk was much higher in the younger group, the absolute risk was greatest among the octogenarians. These increased cardiovascular risks were not confined to subjects with blood pressures greater than 140/90 mm Hg; rather, there was a threshold of risk shown all the way down to 115/75 mm Hg. Even small reductions in blood pressure can have a significant positive impact on cardiovascular disease. Blood pressure reductions of 4 mm Hg systolic and 3 mm Hg diastolic were shown to reduce cardiovascular events by 15% in a cohort of 20,888 patients.

    The Heart Outcomes Prevention Evaluation study asked the question whether all patients with atherosclerosis, regardless of blood pressure, should be treated with an angiotensin-converting enzyme inhibitor. Although many subsequent editorials implied that all patients with CAD could benefit from this therapy, a closer look at the data suggests a different interpretation. The mean blood pressure was 139/79 mm Hg, suggesting that a significant portion of the 9297 participants had a baseline blood pressure higher than this value.

    Compared with placebo, the treatment group had a 22% reduction in the primary outcome composite of myocardial infarction, stroke, or cardiovascular death. A small substudy using 24-hour ambulatory blood pressure monitoring showed blood pressure differences of 11 mm Hg systolic and 4 mm Hg diastolic in the treatment group compared with the placebo group, which may explain the cardiovascular event reductions reported.

    The blood pressure goal for treatment of hypertension in patients with established ischemic heart disease should be < 130/80 mm Hg. One must be careful with aggressive diastolic blood pressure management, as some studies have shown a J-shaped curve relationship between diastolic blood pressures and coronary events.

    Hyperlipidemia

    Dyslipidemia is an important risk factor for atherosclerotic cardiovascular disease, and the lowering of LDL-cholesterol has been shown to correlate with reductions in cardiovascular disease event rates. Previously published cholesterol treatment guidelines recommended achieving less than 70 mg/dL LDL-cholesterol levels in CAD patients. The current guidelines published by the ACC-AHA depart from these specific values, and instead recommend using high- intensity 3-hydroxy-3-methylglutaryl coenzyme reductase inhibitors (statins) to reduce the LDL-cholesterol levels by more than 50%. These agents have been shown to be well tolerated and have positive nonlipid pleiotropic effects as well as the ability to dramatically lower LDL levels.

    Observational evidence suggests that regardless of how cholesterol is lowered, a reduction in atherosclerotic cardiovascular disease will result. However, to achieve meaningful reductions in cardiovascular mortality, the recommended choice for lowering LDL-cholesterol levels among the currently available pharmacologic are the statins.

    These agents have been studied exclusively using fixed dose combinations and not dose titrated to achieve various LDL-c levels; therefore, currently available data does not support specific LDL target goals.

    The Cholesterol Treatment Trialists’ meta-analysis, including 90,056 subjects from 14 trials, showed a 12% reduction in all-cause mortality per 38.6 mg/dL (1 mmol/L) reduction in LDL-cholesterol, with a 19% reduction in coronary mortality, a 24% reduction in need for revascularization, a 17% reduction in stroke incidence, and a 21% reduction in any major vascular event during a mean follow-up period of 5 years. These benefits were observed in different age groups, across genders, at different baseline cholesterol levels, and equally among those with and without prior CAD and cardiovascular risk factors.

    The Heart Protection Study showed that in patients with established CAD, other atherosclerotic vascular disease, or diabetes, statin therapy reduced cardiovascular events regardless of the baseline LDL-cholesterol level. The trial, which enrolled 20,536 patients aged 40 to 80 years, showed a 24% reduction in major cardiovascular events, a 25% reduction in stroke, and a 13% reduction in overall mortality with statin therapy.

    Patients with a recent acute ischemic syndrome were enrolled in the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial, known as Thrombolysis in Myocardial Infarction 22, which compared 80 mg atorvastatin (Lipitor) with 40 mg of pravastatin (Pravachol).

    The atorvastatin group achieved a median LDL level of 62 mg/dL, compared with 96 mg/dL in the pravastatin group. The relative risk reduction for this reduced LDL level was 16%. A substudy looking at the LDL-cholesterol levels achieved with atorvastatin showed that those subjects achieving a level of 40 to 60 mg/dL had a 22% reduction in events, compared with those achieving a level of 80 to 100 mg/dL.

    Therefore, it appears that high-dose statin therapy and aggressive LDL-lowering in this patient population lead to reduced cardiovascular events.

    The Treating to New Targets trial was the first to compare a more intensely treated group with a less intensely treated group using the same agent. The design of this 10,000-patient study eliminated concerns that outcome differences were induced by dissimilar statin preparations. The mean LDL level achieved was 101 mg/dL with 10 mg atorvastatin, and 77 mg/dL with the 80 mg dose. This LDL reduction was associated with a relative risk reduction of 27% for the primary endpoint of the first major cardiovascular event.

    There is an increased risk of myopathy and rhabdomyolysis in patients taking 80 mg simvastatin (Zocor), according to the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH). The FDA has subsequently restricted high- dose simvastatin to patients who have been on this dose for longer than 12 months without evidence of myopathy, and the agency has recommended that new patients should not be started on this particular dose.

    To effectively achieve a greater than 50% LDL-cholesterol reduction in CAD patients utilizing currently available pharmacologic agents, the most recent treatment guidelines suggest either atorvastatin 40 to 80 mg or rosuvastatin (Crestor) 20 to 40 mg. In other patient populations that require moderate-intensity statin therapy, there are several statin choices. Because there is no currently available evidence to suggest that non–statin lipid-altering agents effectively reduce cardiovascular mortality, these medications should not be routinely prescribed.

    It is apparent from both primary and secondary prevention lipid trials that achieving lower LDL levels reduces cardiovascular event rates. Because there is no high-quality clinical evidence to support achieving specific LDL levels in patients with diagnosed CAD, high- dose statin therapy should be the mainstay of pharmacologically based therapy, if tolerated.

    Metabolic Syndrome

    The combined presence of insulin resistance, hypertension, dyslipidemia, and abdominal obesity define metabolic syndrome. There is debate about whether this is a true syndrome or simply a clustering of cardiovascular risk factors in a particular individual. The key concept is that the concomitant presence of these particular cardiovascular risk factors markedly increases a patient’s chances of developing diabetes mellitus and coronary atherosclerosis. The approach to treatment for this syndrome is no different from that for the individual components. Recognition of the components is key to the treatment of this disorder.

    Smoking

    Cigarette smoking is probably the most important of the identified modifiable cardiovascular risk factors. The incidence of CAD is two to four times higher in smokers than in nonsmokers. The pathophysiologic process that leads to atherosclerosis from smoking stems from induced platelet dysfunction, endothelial dysfunction, smooth muscle cell proliferation, and attenuated high-density lipoprotein-cholesterol levels. Smoking cessation must be sought for every CAD patient.

    Diet

    Lifestyle changes for patients with CAD must incorporate healthy eating habits. The Mediterranean diet has been shown to positively affect cardiovascular disease, and conversely, a diet high in saturated fats has been shown to negatively influence multiple cardiac risk factors. Patients should be encouraged to incorporate high proportions of fruits and vegetables into their diet, along with olive oil and regular servings of fish coupled with a reduced amount of red meats.

    Other Lifestyle Changes

    Exercise should be encouraged in patients with stable angina, once all appropriate invasive and noninvasive tests have been completed and a stable medical regimen has been established.

    Increasing a patient’s aerobic capacity can lower the body’s oxygen requirement for a given workload, which can lead to increased exercise tolerance and reduced anginal symptoms. Aerobic exercise can improve endothelial function and positively affect baroreflex sensitivity and heart rate variability in patients with CAD.

    Endorphins released during exercise are thought to be mood enhancers as well as effective muscle relaxants. Exercise itself improves sleep patterns. Cortisol levels are reduced with regular exercise, which may attenuate the body’s sensation of stress and anxiety. For these reasons, appropriate exercise programs for patients with stable angina have far-reaching positive benefits. Exercise guidelines for CAD patients have been published and should be reviewed before patients begin aggressive secondary prevention efforts.

    Major depression affects approximately 25% of people recovering from a myocardial infarction, and another 40% suffer from mild depression. In any given year, one of every three long-term acute ischemic syndrome survivors will develop depression. The Heart and Soul Study examined 1017 patients with stable CAD over a period of 4.8 Patients identified with depression were twice as likely to experience recurrent cardiovascular events. Physical inactivity was associated with a 44% greater rate of cardiovascular events. Patients with symptoms of depression were less likely to follow dietary, exercise, and medication recommendations.

  6. 6
    Approach to Treatment

    Medical Therapy

    Medications used to treat angina pectoris and typical dosages are listed in Table 2.

    Table 2

    Medications Used for the Treatment of Angina Pectoris

    1  Not FDA approved for this indication.

    Nitrates

    Nitrates provide an exogenous source of nitric oxide, which serves to relax smooth muscle and inhibit platelet aggregation. Nitrates exert their antianginal effect by reducing myocardial oxygen demand through coronary and systemic vasodilatation. Nitrates are strong venodilators, and in higher doses they can also induce arterial dilatation. Reducing the preload through venodilatation reduces myocardial oxygen demand. Coronary artery dilatation of stenotic vessels and intracoronary collaterals directly increases myocardial oxygen delivery. Through these mechanisms, nitrates have been shown to prevent recurrent episodes of angina and to increase exercise tolerance.

    There are several nitrate preparations; they differ mainly in route of administration, onset of action, and effective half-life. Nitrate tolerance can occur with long-term use of any nitrate preparation and can be avoided by providing a 10- to 12-hour nitrate-free interval. “Nitrates should be used with caution in patients with a diagnosis of hypertrophic obstructive cardiomyopathy.”

    β-Blockers

    β-Blockers competitively inhibit catecholamines from binding to β- receptors. Over time, β-blocker therapy leads to an increase in β- receptor density. Because of receptor upregulation, acute β-blocker withdrawal may lead to a transient supersensitivity to catecholamines and subsequent angina or even myocardial infarction. There are three classes of β-receptors. Some β-blockers are receptor specific, and some exert an effect over all three receptors. However, at higher doses, even β-selective agents have cross-reactivity for all β-receptors. β-Blockers reduce myocardial oxygen demand through a negative inotropic effect, a chronotropic effect, and a reduction in left ventricular wall stress.

    Several cardioselective β-blockers, including atenolol (Tenormin) and metoprolol (Lopressor), have been shown to be effective antianginals that are fairly well tolerated in patients with underlying bronchospastic disease. Dosing is important for β-blocker efficacy. A study comparing atenolol with placebo showed that all doses from 25 through 200 mg/day were effective in reducing angina, but only the two highest doses led to an increase in exercise tolerance. Certain β-blockers have intrinsic sympathomimetic activity, including pindolol (Visken)1 and acebutolol (Sectral).1 Although they may be effective in reducing angina, they should be used with caution in patients with a prior history of myocardial infarction and in those with left ventricular dysfunction, because they may not reduce heart rate or blood pressure at rest.

    When β-blockers are used to treat angina, a goal resting heart rate should be between 55 and 60 beats/minute. Caution should be used in patients with resting bradycardia and in those with known reactive airway disease. Atenolol is renally excreted and should be used with caution in the elderly and in those with known renal dysfunction.

    Calcium Channel Blockers

    Calcium channel blockers are classified as either dihydropyridines or nondihydropyridines. The former group includes amlodipine (Norvasc), felodipine (Plendil),1 nifedipine (Procardia), and nicardipine (Cardene); the latter includes diltiazem (Cardizem) and verapamil (Calan). There are differences among the two subclasses in regard to chronotropic, dromotropic, and inotropic effects.

    Calcium channel blockers positively alter myocardial oxygen supply and demand, mainly through direct arterial vasodilatation. The nondihydropyridines also exhibit negative chronotropic and inotropic effects, thus further lowering myocardial oxygen demands.

    One of the early quick-release preparations of a dihydropyridine calcium channel blocker, nifedipine, was reported to potentially induce myocardial infarction when used to treat angina. This was most likely due to a rapid drop in afterload leading to reflex adrenergic activation. Sustained-release preparations of nifedipine (Procardia XL), as well as the other dihydropyridines, have been proven safe and effective in patients with cardiovascular disease.

    Although amlodipine and felodipine are tolerated in patients with left ventricular systolic dysfunction, other calcium channel blockers should be avoided in this patient subset.

    Ranolazine (Ranexa)

    Ranolazine (Ranexa) is a new and unique antianginal drug approved for the treatment of stable angina. It is a sustained-release preparation that has been approved for patients who remain symptomatic while on standard angina pharmacotherapy. Its mechanism of action may be through reduction of fatty acid oxidation or effects on sodium shifts and intracellular calcium levels. QT prolongation has been reported, but a significant increase in arrhythmias has not been seen. Side effects include dizziness, constipation, and nausea. Dosing is 500 or 1000 mg twice daily, and the major route of metabolism is the cytochrome P-450 system. Ranolazine should be used cautiously in patients who are taking other pharmacologic agents that have the potential to prolong the QT interval, “and in patients with liver cirrhosis.”

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    Medication Combinations

    Many patients with chronic stable angina require more than one antianginal medication to control their symptoms. “Current guidelines recommend β-blockers or calcium channel blockers as initial therapy unless otherwise contraindicated, with the addition of nitrates as symptoms dictate. Further medications may be added and individualized to each patient based on their degree of angina and overall clinical response.”

    However, it is important to recognize medication side effects when deciding which agents to combine. β-Blockers block the atrioventricular (AV) node and exert a portion of their effectiveness through this mechanism. The nondihydropyridine calcium channel blockers also have AV-nodal blocking properties, and therefore should be used cautiously with β-blockers, especially in patients with preexisting conduction system disease. The dihydropyridine agents do not have AV-nodal blocking effects and may be a safer choice when used in combination with β-blockers. Nitrates do not have a side-effect profile that raises concerns when they are used with β– blockers or with calcium channel blockers.

     

  8. 8
    Antiplatelet Therapy

    The common etiology leading to an acute ischemic syndrome is a platelet-rich clot occurring at the site of a significant coronary artery stenosis, often after a plaque rupture. Antiplatelet medications have been shown to consistently decrease morbidity and mortality in a wide array of cardiovascular disease patients. A meta-analysis suggested that for patients with stable cardiovascular disease, low- dose aspirin therapy (50–100 mg daily) is as effective as higher doses (> 300 mg). In this patient population, aspirin therapy resulted in a 26% reduction in myocardial infarction; the number of patients needed to treat to prevent a myocardial infarction was 83.

    The Antiplatelet Trialists’ Collaboration study demonstrated a reduction in myocardial infarction, stroke, and death in high-risk cardiovascular patients treated with antiplatelet therapy. Consensus guidelines recommend indefinite oral aspirin for the secondary prevention of cardiovascular events in all angina patients.

    Clopidogrel (Plavix)1 is an effective alternative to aspirin for the treatment of stable cardiovascular disease in those patients with a true aspirin allergy. However, there are no compelling data to indicate that clopidogrel (or newer agents, such as prasugrel [Effient]1 and ticagrelor [Brilinta]1) are superior to aspirin in this particular patient population. In patients with unstable angina, dual antiplatelet therapy with aspirin and clopidogrel is recommended.

    Invasive Assessment

    The decision to pursue an invasive treatment approach differs significantly in patients with chronic stable angina and in those with acute coronary syndromes. Within both groups, accurate risk stratification is the key consideration in choosing who will benefit from coronary angiography and subsequent percutaneous coronary intervention. An invasive strategy in unstable angina patients has been shown to reduce recurrent acute coronary syndrome events consistently in many trials. A routine invasive strategy is recommended for patients with non–ST-segment acute ischemic syndromes who have refractory ischemia, elevated cardiac biomarkers suggesting myocardial necrosis, or new ST-segment depression on ECG monitoring.

    In patients with unstable angina, there are significant gender differences in outcomes related to the use of invasive therapy. Both men and women with elevated biomarkers from myocardial necrosis have comparable reductions in rates of death, myocardial infarction, and rehospitalization with invasive treatment strategies. However, in the absence of positive biomarkers, women appear to have potentially negative outcomes with an invasive approach. The current American College of Cardiology and American Heart Association guidelines recommend a conservative approach in such women.

    Patients diagnosed with stable angina comprise a vast array of clinical presentations. The two most heated debates in this arena concern the initial choice of medical therapy versus an invasive approach, and when to cross over from a medical treatment plan to an invasive one. The Atorvastatin Versus Revascularization Treatment (AVERT) trial studied the effects of intensive lipid-lowering therapy on ischemic events in a relatively low-risk population of patients with single- or two-vessel disease compared with percutaneous transluminal coronary angioplasty. AVERT randomized 341 patients to medical therapy plus atorvastatin 80 mg or to angioplasty followed by usual medical care (which included the option of statin therapy at the choice of the treating physician). The medical treatment group experienced a 36% reduction in the composite endpoint of ischemic events compared with the angioplasty group. This difference was due primarily to repeated angioplasty, coronary artery bypass grafting, or hospitalization for worsening angina. The primary outcome of this trial from a practical standpoint was that high-dose statin therapy was safe in this patient population and did not increase cardiovascular events, compared with an angioplasty-based treatment plan.

    One of the keys in interpreting the available data is recognizing that by the time many of these trials are published, the percutaneous treatment choices are often outdated. Early trials used mainly balloon angioplasty; later trials used early-generation bare metal stents.

    Equally as important is to determine what the background medical treatment plans were for any particular trial on this subject. Often, lipid therapy was not aggressive, hypertension management was not confirmed to be adequate, and intravenous glycoprotein IIb/IIIa antagonists were either not available or not used as a standard protocol when indicated.

    The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial was designed to address the potential advantages of current medical therapy over a percutaneous approach in patients with demonstrable ischemia but stable CAD. Of the 35,000 patients screened, only 2287 met the study inclusion criteria. All participants of the COURAGE trial underwent a coronary angiography, and patients with high-risk anatomic findings such as severe left main coronary artery stenosis were excluded. The biggest difference in this trial compared with previous studies was that strict guideline-based medical therapy was followed in both groups. In the entire cohort, 85% of subjects were taking a β-blocker, 93% were taking a statin, and 85% were taking aspirin. The final interpretation of the COURAGE trial results was not that medical therapy is superior for all patients with CAD, but that in selected cohorts, aggressive medical therapy is an appropriate first step in the treatment of ischemic heart disease.

    Novel Therapies

    Transmyocardial Laser Revascularization

    Transmyocardial laser revascularization is an invasive treatment that can be performed as an open-heart procedure or percutaneously. The mechanism was originally thought to be the creation of myocardial channels leading to collateral circulation to ischemic zones, but this concept has been called into question. Current theories suggest cardiac denervation, laser-induced angiogenesis, or placebo effect.

    Likely selection bias within trials has also limited published outcomes data. In a randomized trial involving patients with class III or IV angina and percutaneously untreatable CAD, there was no reduction in angina, no improvement in exercise tolerance, and no decrease in adverse cardiac events after percutaneous transmyocardial laser revascularization, compared with maximal medical therapy. In this trial, the placebo effect was dramatically reduced through extensive blinding protocols for patients and treating physicians.

    Angiogenesis leading to the induction of newly formed coronary vessels has been an active area of research for many years. Three main angiogenic growth factors have been studied: fibroblastic growth factors, vascular endothelial growth factor, and platelet-derived growth factor. Major research limitations for these agents are that they do not act independently, and their biologic properties are poorly understood. Potential complications such as aberrant vascular proliferation, tumor development or proliferation, and proatherogenic effects have made patient enrollment difficult. Although there are some trial results suggesting that the ischemic burden shown on perfusion imaging may be reduced, no firm positive outcome data have yet been published.

    External Counterpulsation

    External counterpulsation is a noninvasive method of increasing coronary blood flow through diastolic augmentation. Large blood pressure cuffs are placed on both legs and thighs and are inflated to a pressure of 300 mm Hg in early diastole (triggered by the patient’s ECG), promoting venous return to the heart. The mechanism is unclear but may be related to enhanced endothelial function, improved myocardial perfusion, and possibly placebo effect. Several small studies have suggested “a clinical reduction in angina episodes, but no positive mortality benefit has yet been published. A meta- analysis that included 13 observational studies and followed 949 patients’ angina class using the CCS classification scheme noted at least a one-class improvement in 86%” of the study population.

    Contraindications to this treatment include certain aortic valvular diseases, aortic aneurysm, and peripheral vascular disease.

    Spinal Cord Stimulation

    For patients whose angina is refractory to medical therapy and who are not candidates for revascularization, spinal cord stimulation may be considered. Little intermediate or long-term data are available, but many short-term studies suggest reduced angina episodes. Placement of the device and subsequent stimulation at the C7-T1 level suggests that the mechanism of action is reduced pain sensation.

    Acupuncture

    Acupuncture has been shown to be of benefit for the relief of both acute and chronic pain in various medical conditions. With respect to patients with documented CAD and symptomatic angina, there is insufficient data currently available to recommend this modality. The difficulty in devising a true blinded study may limit randomized data from being effectively obtained in the future.

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    Other Causes of Angina

    Syndrome X

    The cardiac syndrome X refers to patients who have normal or near- normal epicardial coronary arteries and episodic chest pain. This disorder is much more common in women and is often seen in patients younger than 50 years of age. The chest pain episodes may last longer than 30 minutes and may have a variable response to sublingual nitrates. Patients with syndrome X often describe typical stress-induced angina. Risk factors include hypertension, diabetes, and hyperlipidemia. Female patients are typically postmenopausal and frequently have stress-induced symptoms and ischemia on stress imaging. They often respond to standard angina medications and typically have a better prognosis than patients with significant epicardial plaque.

    Vasospastic or Prinzmetal’s Angina

    The classic definition of Prinzmetal’s angina is chest pain with documented ST-segment elevation during symptoms or during exercise in the face of angiographically normal or near-normal coronary arteries. Over the years, the definition has expanded to include patients who have classic angina symptoms commonly relieved with nitrates or calcium channel blockers and minimal or no CAD. It has been shown that patients with nonobstructive CAD may be prone to focal artery spasm at the stenosis site; therefore, the previous requirement of normal coronary arteries is not an absolute necessity. Other disease states (e.g., Raynaud’s phenomenon) can increase a patient’s development of coronary artery spasm, as can illicit drug usage (e.g., cocaine). Vasospasm is more common in active smokers. β-Blockers should be used cautiously in these patients because they may exacerbate coronary spasm. Patients with angiographically documented intramyocardial bridging may be prone to focal coronary spasm and subsequent angina pectoris.

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    Newer Imaging Techniques

    Calcium Scoring

    Coronary artery calcium scoring is a well-studied imaging modality used to assess a patient’s pretest probability of CAD. With respect to evaluation for angina, one must remember that electron-beam computed tomographic (CT) scanning does not offer physiologic data and therefore does not allow determination of myocardial ischemia.

    This study is most useful in the work-up of a low-risk patient with an atypical chest pain syndrome. If such a patient has an elevated calcium score, other studies may be reasonable “and further assessment of the patients cholesterol values should be performed.”

    CT Coronary Angiography

    CT coronary angiography is a noninvasive way to image the coronary arteries. Like electron-beam CT, it does not provide physiologic data regarding coronary artery perfusion, but it does provide anatomic information such as the presence and percentage of coronary artery stenosis. Although selected patients with stable or unstable angina may be considered candidates for CT angiography, its main utility is to evaluate patients for chest pain who are otherwise at low risk and have a low pretest probability. Because of the volume of intravenous contrast required by CT angiography, the risk of contrast nephropathy must be considered when contemplating this study.

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    Summary

    The approach to the patient with angina should be based on a global assessment and intensive treatment of all identified cardiovascular risk factors. “It is recommended that all patients receive the appropriate dose of statin and antiplatelet therapy.” Noninvasive testing is helpful for an initial diagnosis and to guide the decision for a more invasive approach. Familiarity and adherence to current treatment guidelines is of paramount importance. There are important gender differences that should not be overlooked in the clinical presentation of angina and in the approach to optimal therapy.

     

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    References

    Anderson J.L., Adams C.D., Antman E.M., et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2007;5067:e1–e157.

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    1  Not FDA approved for this  indication.

    1  Not FDA approved for this  indication.

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