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Case PresentationThe following test-and-teach case is an educational activity modeled on the interactive grand roundsapproach. The questions within the activity are designed to test your current knowledge. After eachquestion, you will be able to see whether you answered correctly and will then read evidence-basedinformation that supports the most appropriate answer choice. Please note that these questions aredesigned to challenge you; you will not be penalized for answering the questions incorrectly. At theend of the case, there will be a short post-test assessment based on material covered in the activity.Patient History SW presents to her primary care physician with complaints of episodes of chest discomfort. She is a 62-year-old divorced mother of two who has been suffering from increasing chest discomfort for the past 1-2 years. At first she only noticed the discomfort when she experienced extreme exertion, such as running for the bus, and these symptoms always promptly resolved when she stopped or slowed down. She attributed this to no more than "getting old" and "being out of shape." About 6-9 months ago, she noted that the chest pain episodes had become more frequent, occurring perhaps once or twice per week and precipitated by stress, either physical (walking up and down stairs at home with the laundry) or mental(especially after a days work at her job in a government office), but again always resolved with rest.When the chest discomfort episodes began to occur more than once per week, she was persuadedto visit her primary care physician.Medical HistorySW is overweight (55" height; 174 lb) and smoked cigarettes 1 pack/day for 15 years, although shemanaged to taper off and completely stopped about 5 years ago. She drinks a "very occasional"glass of wine. She admits to having a "poor diet" consisting of high-salt, high-fat foods, with few freshvegetables or fruits, but reports that she takes multivitamins to compensate for her poor diet.
She has a history of hypertension (blood pressure, 160/92 mm Hg), which was diagnosed in her late40s, and she has been relatively adherent to a prescription of enalapril 10 mg and "a diuretic" for thelast 10+ years.Dyslipidemia (total cholesterol, 215 mg/dL; LDL, 138 mg/dL; HDL, 35 mg/dL) was diagnosed during aclinic visit 2 years ago; she takes lovastatin 10 mg daily "when she remembers."The patient has never been seen by a cardiologist or had an echocardiogram.Family HistorySWs father had a fatal myocardial infarction (MI) at age 64, and her mother died at age 68 of lungdisease, which motivated the patient to stop smoking. She has a younger sister, age 58, who is alsooverweight and taking medications for hypertension and abnormal blood cholesterol.Which of the following statements is the most accurate as it relates to chronic stableangina?Episodes typically last longer than 20 minutesIt can be caused by acute pericarditisIt only occurs in patients with clinical atherosclerosisIt occurs when the myocardial oxygen demand exceeds the oxygen supplyBurden of Chronic Stable AnginaHardly a day goes by in a busy clinicians office when he or she is not confronted with a patientcomplaining of chest discomfort. Was it something the patient ate, or is it a life-threatening cardiacemergency -- or is it something in-between? Angina recognition and management are age-old andincreasingly prevalent obstacles for clinicians. Because of the spectrum of medical conditions thatnonspecialists are called on to treat, a case study that reviews the basics of how to diagnose andmanage a presentation of "chest pain" is warranted.Angina pectoris is a clinical syndrome that occurs when the myocardial oxygen demand exceeds theoxygen supply. It usually occurs in patients with a buildup (= 70% stenotic occlusion) ofatherosclerotic plaque in 1 or more coronary arteries. However, angina can also occur in personswith valvular heart disease, hypertrophic cardiomyopathy, and uncontrolled hypertension; it can alsobe present in patients with normal coronary arteries and myocardial ischemia related to vasospasmor endothelial dysfunction, resulting in impaired coronary flow reserve -- a disorder that is believed toinvolve the smaller nutrient arterioles of the subendocardium.
Ischemic heart disease (IHD) is the leading cause of death worldwide and can vary substantially in itsclinical presentation. The clinical spectrum of IHD ranges from complete blockage of at least 1coronary artery, which causes an abrupt interruption of blood flow to the heart muscle resulting in anacute MI, to various lesser degrees of blockage or narrowings, which typically represent lessemergent presentations. An example of the latter is chronic stable angina, which manifests asdiscomfort in the chest, neck, arms, and jaw that generally lasts for 10-15 minutes. It is precipitatedtypically by physical activity or emotional stress and is relieved by rest or nitroglycerin.With an estimated 16 million Americans affected, chronic stable angina is the most commonmanifestation of IHD, and its prevalence is greater in women than in men. Anginal symptomssignificantly impair quality of life and functional status, making routine activities of daily livingburdensome and painful.[2,5] Of importance, the burden of the condition not only stems from itsmorbidity, but more so because of its increased risk for death.[6,7] The economic toll of treatment isalso worth mentioning with aggregate direct and indirect costs approximating $165 billion each year.Chronic stable angina has historically been managed with pharmacologic therapies aimed atreducing vasoconstrictive actions that occur as part of the cellular cascade of events associated withischemia: vasodilation, reduced blood pressure, and reduced heart rate. However, thedemonstrated results from traditional therapies, either alone or in conjunction with revascularization,have shown that many patients still do not achieve the American College of Cardiology/AmericanHeart Association (ACC/AHA) treatment goal of freedom from exertional angina.[2,9,10] In addition,registries and healthcare initiatives document significant underutilization of appropriate therapies.[9,11,12]Given its current status and because of 2 recent developments -- a major trial establishing the bestevidence-based approach to treating stable IHD and the first new pharmaceutical agent approved fortreating stable angina in over 20 years -- the goal of this program is to describe the diagnosis andmanagement of a patient presenting with symptoms secondary to chronic IHD, ie, stable angina.Case NarrativeSWs physician asks the nurse to run a standard electrocardiogram (ECG), and he then asks herseveral questions about the exact nature and quality of her chest discomfort, exactly where it is,when it occurs, and whether she has experienced any associated symptoms.According to the ACC/AHA 2002 guidelines for the management of chronic stable angina,which of the following is considered the most important step in the evaluation of a patientwith chest pain?Assessment of risk factors for coronary artery disease (CAD)Determination of likelihood of CADSymptom severitySymptom location
Predicting the Likelihood of CAD and Ischemic RiskAccording to the ACC/AHA 2002 Guideline Update for the Management of Patients With ChronicStable Angina, the most important first step in the evaluation of a patient who presents with chestpain is the clinical history.When properly conducted, the clinical history allows the clinician to estimate the likelihood ofclinically significant CAD with a high degree of accuracy. The significance of determining thelikelihood of CAD cannot be overstated. As noted in the guidelines, an accurate estimate of thelikelihood of CAD "is necessary for interpretation of further test results and good clinical decisionmaking about therapy."The first step, a detailed description of the symptom complex, enables the clinician to characterizebetween cardiac vs noncardiac etiologies. Five components are typically considered: • Symptom characterization; • Site and distribution; • Provocation; • Duration; and • Factors that relieve the discomfort.As described above, classic (typical) angina is usually characterized by a feeling of discomfort(pressure, squeezing, tightness, heaviness, etc) in the chest, or discomfort in the jaw, shoulder, back,or arm, which usually lasts up to 10 minutes. It is typically aggravated by exertion or emotionalstress, and confirmed for a clinician when it is relieved rapidly by rest or by sublingual nitroglycerin.The severity of symptoms does not correlate with the severity of CAD, but should be assessed tofacilitate diagnosis and treatment decisions (Table 1).Table 1. Classification of Angina Severity According to the Canadian Cardiovascular SocietyClass Level of SymptomsClass I Ordinary activity does not cause angina (Angina with strenuous, rapid, or prolonged exertion only)Class II Slight limitation of ordinary activity (Angina on walking or climbing stairs rapidly, walking uphill, or exertion after meals, in cold weather, when under emotional stress, or only during the first few hours after awakening)Class Marked limitation of ordinary physical activityIII (Angina on walking 1 or 2 blocks on the level or 1 flight of stairs at a normal pace under normal conditions)Class Inability to carry out any physical activity without discomfort or angina at restIVAnginal equivalents, such as exertional dyspnea, sweating, excessive fatigue, and fainting, arecommon in women and in the elderly. Women frequently present with atypical complaints; women
may report variable pain thresholds, inframammary pain, palpitations, or sharp stabbing pain. Suchatypical presentations have unfortunately led to frequent underdiagnoses and undertreatment in thisvulnerable population.[15-17]Symptom history can be used to clinically classify the pain as typical angina, atypical angina, ornoncardiac chest pain (Table 2).[2,13,18] Of note, the probabilities for noncardiac chest pain and atypicalangina are significantly more likely in primary care practice. Patients with noncardiac chest pain aregenerally at lower risk for IHD.Table 2. Clinical Classification of Chest PainType CharacteristicsTypical angina (1) Substernal chest discomfort with a characteristic quality and duration that are (2)(definite) provoked by exertion or emotional stress, and (3) relieved by rest or nitroglycerinAtypical Meets 2 of the above characteristics(probable)Noncardiac chest Meets 1 or none of the typical anginal characteristicspainWhen used in combination with age and sex, this simple approach to categorize pain type serves forsecondary stratification to determine the likelihood that symptoms are secondary to CAD (Table 3).[2,18] This model, however, was established on university-based studies, and caution should beexercised when applying it in a primary care setting for patients who present for the first time withchest pain complaints.Table 3. Pretest Likelihood of Coronary Artery Disease in Symptomatic Patients, According toAge and SexAge (yrs) Nonanginal Chest Pain Atypical Angina Typical Angina Men Women Men Women Men Women % 30-39 4 2 34 12 76 26 40-49 13 3 51 22 87 55 50-59 20 7 65 31 93 73 60-69 27 14 72 51 94 86Each value represents the percentage of patients with significant coronary artery disease oncatheterization.In addition to symptom history, estimating the likelihood of CAD should also include assessment oftraditional coronary risk factors.[2,13] However, risk factors should not be the primary contributor todetermining the likelihood that symptoms are secondary to CAD. The guidelines recommend thatdifferential diagnoses be considered in patients with risk factors for CAD but who otherwise have alow probability of a history of angina (Table 4).
Table 4. Alternative Diagnoses to Angina for Patients With Chest Pain Nonischemic Cardiovascular Pulmonary Gastrointestinal Chest Wall PsychiatricAortic dissection Pulmonary Esophageal Costochondritis Anxiety disordersPericarditis embolus Esophagitis Fibrositis Hyperventilation Pneumothorax Spasm Rib fracture Panic disorder Pneumonia Reflux Sternoclavicular Primary anxiety Pleuritis Biliary arthritis Affective disorders Colic Herpes zoster (eg, depression) Cholecystitis (before the rash) Somatoform disorders Choledocholithiasis Thought disorders Cholangitis (eg, fixed delusions) Peptic ulcer PancreatitisThe ACC/AHA guidelines stipulate that a resting ECG should also be performed in all patients withsymptoms suggestive of angina. However, the ECG will be normal or not diagnostic inapproximately 50% of patients with chronic stable angina. A normal rest ECG should not excludesevere CAD.[2,18]Case Narrative (Continued)Table 5 shows SWs lab results.Table 5. Laboratory Values Laboratory ValuesLDL-C (mg/dL) 110HDL-C (mg/dL) 38Total-C (mg/dL) 220TG (mg/dL) 180Creatinine 1.1Fasting glucose (mg/dL) 103A1c (%) 5.8Other observations:No evidence of heart failure in physical examECG: normalOn the basis of the patients presenting complaints, SWs physician categorizes her symptoms astypical angina. Coupled with her age and sex, she is believed to be at intermediate risk for CAD. Thepatient is stable, not currently symptomatic, and is able to exercise. SWs physician now has toassess how her chest pain translates into a level of CAD risk for a future coronary event and themost effective testing to help determine that risk.
According to the ACC/AHA guidelines, which of the following should be the initial testingmodality for this patient with an intermediate probability of CAD?Exercise ECG stress test (without imaging)Exercise stress test with imagingMyocardial perfusion imaging (MPI) with thalliumDobutamine echocardiographyCoronary angiographyDetermining Ischemic RiskOnce the clinician has determined that the patients chest pain is likely due to ischemia, the next stepis to obtain a definitive diagnosis of CAD. The ACC/AHA guidelines underline the importance ofmatching the intensity of evaluation method against a patients estimated probability of CAD. (Forpatients with chest discomfort suggestive of CAD but a low probability of events, the decision topursue further testing should be based on a shared discussion between the patient and the clinician.)Patients who are estimated to have an intermediate or high likelihood of CAD (> 10%-20%probability; Table 4) should undergo further risk stratification testing with noninvasive and/or invasivestrategies, as indicated. Noninvasive testing can include exercise ECG stress testing, MPI withsestamibi or thallium, and stress echocardiography. Invasive evaluation includes coronaryangiography.Generally, all patients with an intermediate-to-high probability of CAD should undergo stress testing,with exercise as the preferred form of stress. (Of note, the inability to exercise is in itself a negativeprognostic factor.) The choice of test will depend on several variables: For example, can the patientexercise on a treadmill or bicycle to a level high enough for exertion? Is the baseline ECG normal orabnormal? Is the patient taking digoxin? Has the patient previously undergone revascularization?These considerations will dictate whether a standard exercise treadmill stress test, MPI, or possiblycoronary angiography should be performed (Table 6).[2,13]Table 6. Recommendations for Initial Noninvasive Test for Risk StratificationTest Recommended Not RecommendedExercise ECG testing (using Symptomatic patients with Baseline ECG abnormalities (Wolff-the Bruce protocol and Duke intermediate-to-high probability of Parkinson-White syndrome,treadmill score) CAD who are able to exercise and electronically paced ventricular not taking digoxin (LOE: B) rhythm, > 1 mm ST depression at rest, LVH, or complete LBBB) (LOE: After significant change in anginal B) pattern (LOE: C) Established diagnosis of CAD (prior MI, angiography) (LOE: B)Cardiac stress imaging (able Patients with intermediate pretest Patients with LBBB or cardiacto exercise) -- exercise MPI probability of CAD with abnormal pacing device (LOE: B)or exercise results on resting ECG or are
echocardiography using digoxin (LOE: B)Cardiac stress imaging Patients with an intermediate Dobutamine echocardiography not(unable to exercise) -- pretest probability of CAD (LOE: recommended in patients with LBBBadenosine or dipyridamole B) or in patients with prior or cardiac pacing device (LOE: B)MPI or dobutamine revascularization (LOE: B), but doechocardiography not have LBBB or a cardiac pacing deviceCardiac stress imaging -- Patients with LBBB or with cardiacadenosine or dipyridamole pacing device (regardless ofMPI ability to exercise) (LOE: B)CAD = coronary artery disease; ECG = electrocardiographic; LBBB = left bundle branch block; LOE= level of evidence; LVH = left ventricular hypertrophy; MPI = myocardial perfusion imagingECG exercise stress testing is the most commonly employed test for risk stratification in stable IHD.When performed in patients with an intermediate pretest probability of CAD, ECG exercise testinghas the largest effect on post-test probability and, in turn, on clinical decision making (Class I, level ofevidence [LOE]: B). Although less useful for a diagnosis in patients with a high pretest probability,the test results can be used to determine a patients risk and prognosis. Interpretation of theexercise test should include symptomatic response, exercise capacity (duration and intensity),hemodynamic response, and changes in ECG during or after testing. Positive exercise stress testingis most commonly defined as ST-segment depression (= 1 mm of horizontal or downsloping) or STelevation (= 60-80 msec after the end of the QRS complex).[2,18]Coronary angiography is typically recommended for patients in whom there is a strong suspicion thatthere is significant (or extensive) CAD and in whom noninvasive testing is contraindicated or unlikelyto have reliable results. The decision to move forward with coronary angiography can also beguided by the performance of noninvasive tests. For example, a patient with a high-risk treadmillstress test is likely indicated for coronary angiography. Similarly, coronary angiography may beappropriate in a patient with abnormal, but not definitely diagnostic noninvasive test results whowould benefit from a more certain diagnosis (Class IIa, LOE: C).Diagnostic Modalities for CAD in WomenThe utility of ECG stress testing in women is a topic of debate. The rate of false positives has beenshown to be higher in women than men, and may be attributed to differences in criteria for definingcoronary disease, prevalence of multivessel disease and prior MI, type and intensity of exercise,prevalence of nonobstructive CAD, and hormonal differences.[2,19] Exercise imaging modalities areknown to have a greater diagnostic accuracy than standard exercise stress tests in both men andwomen, leading some to suggest that imaging exercise testing be the preferred test to diagnose CADin women. However, the ACC/AHA guidelines note that there are insufficient data to support such arecommendation. In addition, diagnostic angiography is equally effective in women and men, yetstudies have documented lower rates of referral for angiography in women despite positive stresstests.
Ultimately, the type of test to employ should be based on a comprehensive assessment of likelihoodof CAD while considering the specificity and sensitivity of the testing modality, as well as patientpreference and comorbidities.Determining Ischemic Risk Based on Diagnostic StudiesA patients ischemic risk is usually related to 4 variables: (1) left ventricular (LV) function, (2)anatomic extent and severity of atherosclerosis, (3) evidence of a recent coronary plaque rupture,and (4) patients general health and noncoronary comorbidity.For patients with stable angina, the presence of diabetes, hypertension, dyslipidemia (increasedLDL-C and/or decreased HDL-C), current smoking, metabolic syndrome, and peripheral arterialdisease have been shown to be predictive of increased risk. Such factors suggest a greaterprogression of atherosclerosis with the potential for repeated coronary plaque events. Increasing ageis an important factor to consider, as are prior MI, symptoms and signs of heart failure, the pattern ofoccurrence (recent onset or progressive), and severity of angina -- particularly if unresponsive totherapy.Whereas noninvasive testing modalities can be used for risk stratification, the guidelines note thatrisk stratification with coronary angiography may be limited by the fact that the testing cannotdetermine which plaques are likely to lead to subsequent rupture. The ACC/AHA guidelinesrecommend the use of coronary angiography for risk stratification in patients with disabling chronicstable angina despite chronic therapy (Class I, LOE: B), in patients with high-risk criteria onnoninvasive testing (Class I, LOE: B; Table 7), and in those with signs and symptoms of congestiveheart failure (Class I, LOE: C) or clinical characteristics that indicate a high likelihood of severe CAD(Class I, LOE: C).Table 7. Noninvasive Risk StratificationHigh-Risk (> 3% annual mortality rate)• Severe resting left ventricular dysfunction (LVEF < 35%)• High-risk treadmill score (score = -11)• Severe exercise left ventricular dysfunction (exercise LVEF < 35%)• Stress-induced large perfusion defect (particularly if anterior)• Stress-induced multiple perfusion defects of moderate size• Large, fixed perfusion defect with LV dilation or increased lung uptake (thallium-201)• Stress-induced moderate perfusion defect with LV dilation or increased lung uptake (thallium-201)• Echocardiographic wall motion abnormality (involving > 2 segments) developing at low dose ofdobutamine (= 10 mg/kg/min) or at a low heart rate (< 120 beats/min)• Stress echocardiographic evidence of extensive ischemiaIntermediate-Risk (1%-3% annual mortality rate)• Mild/moderate resting left ventricular dysfunction (LVEF = 35%-49%)• Intermediate-risk treadmill score (-11 < score < 5)• Stress-induced moderate perfusion defect without LV dilation or increased lung intake (thallium-201)• Limited stress echocardiographic ischemia with a wall motion abnormality only at higher doses ofdobutamine involving = 2 segmentsLow-Risk ( < 1% annual mortality rate)
• Low-risk treadmill score (score = 5)• Normal or small myocardial perfusion defect at rest or with stress*• Normal stress echocardiographic wall motion or no change of limited resting wall motionabnormalities during stress*LV = left ventricular; LVEF = left ventricular ejection fraction*Although the published data are limited, patients with these findings will probably not be at low riskin the presence of either a high-risk treadmill score or severe resting LV dysfunction (LVEF < 35%).Case NarrativeSWs physician concludes that her angina is stable, and she is not really at imminent risk for acoronary event. He, therefore, decides that she does not need to be admitted or referred for acoronary angiogram. He discusses this conclusion with her, per guidelines, but advises additionalnoninvasive testing in order to get a better idea of the severity of her chest pain (ie, when, howquickly, and how acutely), and whether there is objective evidence of inducible myocardial ischemia.She agrees, and he sends her for exercise ECG testing, using the Bruce protocol and Duke treadmillscore as a means of quantifying her response to graded exercise.SWs stress testing results come back and confirm a diagnosis of CAD:Resting heart rate: 80 bpmExercise heart rate: 142 bpmTime on treadmill: 9 min 30 secBlood pressure: 185/92 mm HgAt peak exercise, she exhibits 1.5 mm horizontal ST-segment depression in leads II, III, and aVFconsistent with inferior wall subendocardial ischemia at a fairly high external workload.Which of the following is not a primary goal of therapy for patients with chronic stable CAD?Increase blood oxygen supplyIncrease quantity of life by disease modification and prevention of MI and deathImprove quality of life by reducing ischemia and relieving anginal symptomsTreatment of Chronic Stable AnginaThere are 2 primary objectives in managing the patient with stable IHD. The first is to increase thequantity of life by reducing the risk for ischemic events with lifestyle modification and
vasculoprotective therapies. The second goal is to improve the quality of life by reducing the burdenof symptoms through the use of anti-anginal and anti-ischemic agents.Vasculoprotective TherapiesInstituting a treatment protocol aimed at directly treating the pathophysiology of stable IHD is acritical step in the management of the patient with stable IHD. Vasculoprotective therapy includeslifestyle changes (eg, cigarette smoking cessation, appropriate diet, weight reduction/maintenance,regular exercise, etc) and pharmacologic therapy with aspirin, angiotensin-converting enzyme (ACE)inhibitors, and statins, which -- in the aggregate -- reduce progression of atherosclerosis, stabilizeatherosclerotic plaque, and decrease the risk for plaque rupture and superimposed total or subtotalthrombotic occlusions in patients with chronic stable angina. The ACC/AHA guidelinerecommendations for cardiovascular risk reduction in patients with stable CAD are shown in Table 8.Table 8. ACC/AHA Guideline Recommendations for Cardiovascular Risk Reduction in PatientsWith Stable Coronary Artery DiseaseRisk Factor RecommendationsSmoking Complete cessation; no exposure to environmental tobacco smokeBlood pressure < 140/90 mm Hg or < 130/80 mm Hg if patient has diabetes or chronic kidneycontrol diseaseLipid - LDL-C < 100 mg/dL; reduction of LDL-C < 70 mg/dL or high-dose statin therapy ismanagement reasonable/desirable in high-risk patients - If baseline LDL-C = 100 mg/dL, LDL-lowering drug therapy should be initiated in addition to therapeutic lifestyle changes - If on-treatment LDL-C is = 100 mg/dL, LDL-lowering drug therapy should be intensified (may require combination therapy) - If triglycerides are 200-499 mg/dL, non-HDL-C should be < 130 mg/dL (therapeutic options for reducing non-HDL-C include niacin or fibrate therapy) - If triglycerides are = 500 mg/dL, therapeutic options to lower levels to reduce the risk for pancreatitis are fibrate or niacin; these should be initiated before LDL-C- lowering therapy. The goal is to achieve non-HDL-C < 130 mg/dL, if possiblePhysical activity - 30-60 min, 7 days/wk (minimum, 5 days/wk) - Moderate-intensity aerobic activity should be encouraged on all days of the week, supplemented by an increase in daily activitiesWeight Body mass index: 18.5-24.9 kg/m2management Waist circumference: - Men: < 40 in - Women: < 35 inDiabetes HbA1c < 7%managementAntiplatelet Aspirin should be started at 75-162 mg/day and continued indefinitely in all patientsagents unless contraindicatedACE inhibitors ACE inhibitors should be started and continued indefinitely in all patients with left ventricular ejection fraction ≤ 40% and in those with hypertension, diabetes, or chronic kidney disease, unless contraindicatedARBs Use in patients who are intolerant of ACE inhibitors and have heart failure or have had a myocardial infarction with left ventricular ejection fraction ≤ 40%
Aldosterone Use in patients post MI, without significant renal dysfunction or hyperkalemia, whoblockade are already receiving therapeutic doses of an ACE inhibitor and beta-blocker, have a left ventricular ejection fraction ≤ 40%, and have either diabetes or heart failureInfluenza An annual influenza vaccination is recommended for patients with cardiovascularvaccination diseaseACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; HbA1c = glycatedhemoglobin (A1c); MI = myocardial infarctionTraditional Anti-anginal and Anti-ischemic Therapies in Stable AnginaIn addition to the importance of reducing ischemic risk with lifestyle modification and appropriatetherapies, the second major objective in the management of stable IHD is to reduce the burden ofangina (symptom intensity and frequency). Traditional therapies include nitrates, beta-blockers,calcium channel blockers (CCBs), and combinations thereof.NitratesNitroglycerin was the first medication to be used for angina more than a century ago. Nitrates reducemyocardial oxygen demand by increasing venous capacitance, thus reducing LV volume (preload).Nitrates dilate coronary arteries and favorably enhance subendocardial perfusion. Sublingualnitroglycerin has been used to treat the acute onset of anginal symptoms as well as prophylacticallyto minimize or prevent anginal symptoms when these agents are administered in advance of theknown offending activity.Isosorbide dinitrate and its active metabolite, isosorbide mononitrate, are used as an oral preparationfor the treatment of angina. Extended-release preparations offer the convenience of once-dailyregimens. None of the nitrate regimens provide 24-hour anti-anginal prophylaxis due to thedevelopment of nitrate tolerance. Prevention of tolerance requires an intermittent dosing strategywith a nitrate-free interval of 8-12 hours. Nitrates are generally well tolerated, with facial flushing andheadache being the most common side effects. Severe hypotension may occur if nitrates are usedwithin 24 hours of phosphodiesterase inhibitors (sildenafil, tadalafil, and vardenafil).[2,25]Beta-blockersIn the setting of stable IHD, beta-blockers are recommended as initial therapy for patients with priorMI (Class I, LOE: A) or without prior MI (Class I, LOE: B). Beta-blockers reduce heart rate andcontractility and reduce myocardial oxygen demand. Reduction in heart rate increases the diastolicfilling time during which nutritive coronary flow occurs, enhancing myocardial tissue perfusion. Beta-blockers limit increases in heart rate during exercise and are particularly effective in exercise-inducedangina.All beta-blockers are equally effective in alleviating angina pectoris, although optimal doses mayvary. The doses of beta-blockers must be titrated to increase exercise tolerance and reducesymptoms of angina while avoiding unwanted side effects. Prominent side effects include
bradycardia, bronchoconstriction, fatigue, depression, impotence, and worsening of peripheralvascular disease. Despite concerns about their side effects, beta-blockers can be safely used inmany patients with chronic obstructive pulmonary disease or peripheral arterial disease.Calcium Channel BlockersA variety of CCBs have been studied in the long-term treatment of chronic stable angina. CCBs blockthe entry of calcium into the myocardial and vascular smooth muscle cells and promote bothcoronary and peripheral vasodilation.Calcium antagonists include 2 general subclasses of agents: dihydropyridines andnondihydropyridines. Dihydropyridines (eg, nifedipine, amlodipine, and nicardipine) have aproportionately greater effect on vascular smooth muscle and are particularly effective in reducingsystemic arterial blood pressure. Results of a prior meta-analysis indicated that the use of thesedrugs for hypertension does not increase morbidity and mortality. Dihydropyridines reduce thefrequency of anginal episodes, improve exercise duration, and reduce the need for nitroglycerin.Nondihydropyridines (verapamil and diltiazem) affect conduction through the AV node and have anegative chronotropic action. Verapamil, diltiazem, and short-acting nifedipine are effective invasospastic (Prinzmetals) angina. However, short-acting nifedipine is associated with an increasedincidence of cardiovascular events and is not recommended for patients with unstable angina oracute coronary syndrome. On the other hand, verapamil, diltiazem, and long-acting dihyropyridines(eg, amlodipine, extended-release nifedipine) have been shown to be safe and effective in treatingstable angina.Combination TherapyCombinations of anti-anginal drugs may be used if symptoms persist. Beta-blockers and nitrates maybe more effective than nitrates or beta-blockers alone. Similarly, the combination of beta-blockerswith dihydropyridine CCBs has been shown to be more effective for improving exercise duration andis better tolerated than either class of drug used alone. No data exist, however, on the efficacy ofusing more than 2 drugs. Certain drug combinations should be avoided because of the potential foradverse effects, including hypotension or bradycardia. Newer agents may offer additionalpharmacologic benefit in combination with traditional anti-anginal medications.Case NarrativeAt this point, SWs noninvasive stress testing confirms a degree of ischemia, but not of sufficientdegree to mandate further invasive testing to identify the location and degree of coronary obstruction.Her ischemia seems stable, and therefore it is appropriate to prescribe a full course of optimalmedical treatment, per treatment guidelines.Looking over her chart, the physician notes that she admits to a poor diet, plus quasi-adherence to aregimen of 10 mg enalapril plus a diuretic as well as a low-dose, low-potency statin. The physicianstrongly advises SW to improve her diet, and asks his nursing staff to follow up with further advice
and some information handouts. Because she doesnt exhibit signs of heart failure, and he believesthat it may be affecting her overall adherence, he cancels the diuretic. He now switches the ACEinhibitor therapy to ramipril 10 mg/day and adds amlodipine 5 mg/day plus aspirin 162 mg/day. Hetells SW that this therapy should help her reach a target blood pressure of 120/80 mm Hg and atarget total/LDL cholesterol of 175/100 mg/dL, and he explains the importance of remaining adherentto her regimen to protect her against future events ("heart attack") as she grows older.Which of the following statements about nontraditional (ie, ranolazine, ivabradine, andnicorandil, trimetazidine, and fasudil) anti-anginal agents is most accurate?Mechanisms of action complement the anti-ischemic properties of traditional agentsThey reduce the risk for mortality compared with traditional agentsThey are more effective as single- vs combination-drug therapyThey are similarly effective in patients with stable and unstable anginaNovel Anti-anginal TherapiesNovel Anti-anginal TherapiesDespite intensive escalation of anti-anginal therapy, including combinations of beta-blockers, long-acting nitrates, and CCBs, a fair number of patients continue to experience persistent or refractoryangina. A greater understanding of the pathophysiologic pathways associated with chronic stableangina has led to the development of novel agents that target those specific pathways. Of note, themechanisms of action of these newer drugs are complementary to those of the traditional anti-anginal agents. Such agents include ranolazine, ivabradine, and nicorandil, trimetazidine, andfasudil.RanolazineRanolazine is a late sodium (Na+) current inhibitor that has anti-anginal and anti-ischemic effectswithout eliciting any change in the heart rate, blood pressure, or rate-pressure (double) product.Myocardial ischemia causes an exaggerated, enhanced late inward Na+ current, which leads tointracellular sodium overload, which, in turn, leads to intracellular calcium overload, resulting inincreased diastolic LV stiffness as well as electrical instability. By inhibiting the abnormal increase inthe late inward sodium current, the agent prevents the "downstream" consequences of ischemic LVstiffness and compression of intramyocardial blood vessels, which reduces myocardial ischemia.The results from 4 randomized trials (in over 8000 randomized patients) showed a convincing benefitof ranolazine as either monotherapy or as add-on therapy.[32-35] The cumulative effect of these 4 trialsis a consistent clinical benefit on angina relief, reduced exercise-induced ischemia, a significantreduction in recurrent ischemia, and a reduction in the need for additional anti-anginal medication.
The largest of these studies, the Metabolic Efficiency with Ranolazine for Less Ischemia in NSTEACS (MERLIN-TIMI 36) trial, randomized 6560 patients with moderate- to high-risk NSTEMI (amore clinically unstable population) to either ranolazine or placebo in addition to standard care andfollowed them for a median of 1 year. The primary efficacy endpoint was a composite ofcardiovascular death, MI, or recurrent ischemia through the end of the study. Similar to the use oftraditional agents, such as nitrates and CCBs, use of ranolazine was not associated with a reductionin the trials primary composite endpoint of death, MI, or recurrent myocardial ischemia. However,ranolazine was shown to significantly reduce the secondary endpoint of recurrent myocardialischemia compared with traditionally treated patients.As a result of its multiple effects on transmembrane ion currents, ranolazine slightly prolongs the QTinterval, although this has not been shown to increase the risk for torsades de pointes. Ranolazineis approved by the US Food and Drug Administration for the treatment of stable angina alone or incombination with other anti-anginal therapies. Dosing should be initiated at 500 mg twice daily andincreased to maximum dose of 1000 mg twice daily on the basis of clinical symptoms. Dizziness andnausea are the most commonly reported side effects. The drug should not be used in combinationwith strong inhibitors or inducers of CYP3A or in patients with clinically significant hepaticimpairment.IvabradineThe If current ("f" is for "funny," as the current is still poorly understood) is an inward Na+/K+ currentthat activates pacemaker cells of the sinoatrial (SA) node. Ivabradine is a novel, specific heart rate-lowering agent that acts on SA-node cells by selectively inhibiting pacemaker If current in a dose-dependent manner. It slows the diastolic depolarization slope of the SA-node cells and reduces heartrate during rest and exercise. In patients with chronic stable angina, ivabradine monotherapy (7.5 mgtwice daily and 10 mg twice daily) has been shown to be noninferior to atenolol or amlodipine inall tested exercise parameters. More recently, the ASSOCIATE trial demonstrated that ivabradinein combination with atenolol significantly improved exercise parameters after 4 months of therapycompared with atenolol alone. The most common side effect reported with ivabradine is sinusbradycardia; other side effects include luminous phenomena (phosphenes), which are described as atransient enhanced visual brightness, headaches, and blurred vision.[38-41]NicorandilNicorandil activates the adenosine triphosphate (ATP)-sensitive K+ channels, which play an importantrole in ischemic preconditioning and promote dilation of the coronary resistance arterioles. Its nitratemoiety dilates epicardial coronary vessels and systemic veins. In the Impact Of Nicorandil in Angina(IONA) trial, the addition of nicorandil to standard anti-anginal therapy was associated with asignificant (17%) reduction in the primary endpoint of coronary heart disease, death, nonfatal MI, orunplanned hospitalization for cardiac chest pain compared with placebo, suggesting that the drugmay have cardioprotective properties.Trimetazidine
Trimetazidine is a metabolic modulator and partial fatty acid oxygenation inhibitor that has beenproven to be beneficial for combination therapy in patients with stable angina. Oxygen requirementsof glucose pathways are lower than the free fatty acid pathway. During ischemia, oxidized free fattyacid levels rise, which blunt the glucose pathway. Trimetazidine inhibits beta-oxidation and shifts theequilibrium toward increased use of glucose, thus improving oxygen utilization. In the Trimetazidinein Angina Combination Therapy (TACT) trial, trimetazidine in combination with long-acting nitrates orbeta-blockers was shown to significantly improve exercise performance as well as reduce thenumber of anginal attacks per week compared with placebo.FasudilRho kinase in the myocardial cell triggers vasoconstriction through accumulation of phosphorylatedmyosin. Animal models of coronary artery spasm have shown that Rho kinase inhibitors effectivelysuppress vasoconstriction. Fasudil, an orally available Rho kinase inhibitor, increased the time to > 1mm ST-segment depression and improved exercise duration. Fasudil did not affect the heart rateor blood pressure and was well tolerated.The results of the Clinical Outcomes Utilizing Revascularization and Aggressive DrugEvaluation (COURAGE) trial most closely support which of the following statements as itrelates to patients with stable chronic CAD?Optimal medical therapy (OMT) should be the strategy of choice in all patients with stableCADPercutaneous coronary intervention (PCI) should not play a major role in secondaryprevention in patients with stable CADPCI is associated with significant reductions in death and MI compared with OMT aloneObjective evidence of inducible myocardial ischemia on noninvasive testing is notnecessary before PCIPCI for Chronic Stable AnginaIn addition to medical management, the ACC/AHA guidelines recommend revascularization withcoronary artery bypass graft surgery or PCI in some patients with chronic stable angina. Thedecision to proceed with revascularization requires a careful balance of many factors, namely, patientpreference and physician judgment. Of note, it entails a careful balance ensuring that the patientwould have a significantly better prognosis with revascularization than with medical therapy.Despite ACC/AHA recommendations that reserve PCI for patients who remain symptomatic despiteOMT or for those with high-risk criteria on noninvasive testing (Table 9), the practice of simply
referring a stable angina patient for angiography (before noninvasive testing) or for PCI (before initialcourse of medical therapy) is an all too frequent occurrence for many clinicians.Table 9. ACC/AHA Class I Recommendations for PCI in Stable Chronic AnginaClass I RecommendationPatients with 2- or 3-vessel disease with significant proximal LAD CAD, who have anatomy suitable forcatheter-based therapy and normal LV function who do not have treated diabetes (LOE: B)Patients with 1- or 2-vessel CAD without significant proximal LAD CAD, but with a large area of viablemyocardium and high-risk criteria on noninvasive testing (LOE: B)Patients with prior PCI with either recurrent stenosis or high-risk criteria on noninvasive testing (LOE:C)Patients who have not been successfully treated by medical therapy and can undergorevascularization with acceptable risk (LOE: B)CAD = coronary artery disease; LAD = left anterior descending; LOE = level of evidence; LV = leftventricular; PCI = percutaneous coronary interventionA challenge today in the United States is how to address the huge increase in the number of PCIprocedures being performed every year. In 2006, more than 1.31 million PCI procedures wereperformed, roughly 3 times the number of procedures being performed 10 years earlier, and 3important statistics stand out. Roughly half of these procedures were in persons > 65 years of ageand roughly half were elective. In addition, the total cost of these procedures to Medicare in 2005was estimated to be about $20 billion. The fact that almost half of PCIs are elective raises thequestion: Were they medically necessary? According to the New York State PCI Registry, 85% of thePCI procedures in 2006 were elective, almost one third of those in patients with chronic stableangina, and these rates are mirrored in the US national data. However, according to data from aMedicare claims database, only 44% of patients who presented with stable CAD or chronic angina in2004 underwent a noninvasive study, such as an ECG stress test, to assess the degree of ischemiabefore they were referred for an elective PCI procedure. From these statistics it is evident thatmany patients who presented with chronic stable angina were being referred to the cath lab andemerging having been treated with a PCI procedure. The empirical question was whether thesepatients with stable angina, when they have not been first diagnosed with objective evidence ofinducible myocardial ischemia or treated intensively with OMT, really needed, or benefited from, PCI.COURAGEThis hypothesis was tested in the COURAGE trial, which enrolled 2287 patients who had objectiveevidence of myocardial ischemia and significant CAD at 50 US and Canadian centers. Between 1999and 2004, 2287 patients who had objective evidence of myocardial ischemia and significant CADwere randomized to undergo PCI with OMT (PCI group; n = 1149) or to receive OMT alone (OMTgroup; n = 1138). The primary outcome was death from any cause and nonfatal MI during follow-up(mean follow-up of 4.6 years).
All patients received the standard course of anti-anginal therapy. Patients undergoing PCI receivedaspirin and clopidogrel, in accordance with accepted treatment guidelines and established practicestandards. Medical anti-ischemic therapy in both groups included long-acting metoprolol, amlodipine,and isosorbide mononitrate, alone or in combination, along with either lisinopril or losartan asstandard secondary prevention. All patients received aggressive therapy to lower LDL-C levels with atarget level of 60-85 mg/dL. After the LDL-C target was achieved, an attempt was made to raiseHDL-C to > 40 mg/dL and to lower triglycerides to < 150 mg/dL with exercise and extended-releaseniacin or fibrates, alone or in combination. In patients undergoing PCI, target lesion revascularizationwas always attempted, and complete revascularization was performed as clinically appropriate.Success after PCI as seen on angiography was defined as normal coronary artery flow and < 50%stenosis in the luminal diameter after balloon angioplasty and < 20% after coronary stentimplantation. Clinical success was defined as angiographic success plus the absence of in-hospitalMI, emergency coronary artery bypass graft, or death. Drug-eluting stents were not approved forclinical use until the final 6 months of the study; therefore, few patients received these intracoronarydevices.The study found that as an initial management strategy in patients with stable IHD, the addition ofPCI to OMT did not reduce the cumulative rates of MI and death (19.0% vs 18.5%) or in all-causedeath (7.6% vs 8.3%) compared with OMT alone (Figure). Subsequent analyses demonstrated thatthe addition of PCI to OMT was not cost-effective and had only a small (significant) incrementalbenefit in quality of life that did not extend beyond 36 months.
Figure. Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE):Kaplan-Meier survival curves.In Panel A, the estimated 4.6-year rate of the composite primary outcome of death from any causeand nonfatal myocardial infarction was 19.0% in the PCI group and 18.5% in the medical-therapygroup. In Panel B, the estimated 4.6-year rate of death from any cause was 7.6% in the PCI groupand 8.3% in the medical-therapy group. In Panel C, the estimated 4.6-year rate of hospitalization foracute coronary syndrome (ACS) was 12.4% in the PCI group and 11.8% in the medical-therapygroup. In Panel D, the estimated 4.6-year rate of acute myocardial infarction was 13.2% in the PCIgroup and 12.3% in the medical-therapy group.In addition to generating considerable discussion and debate, the COURAGE trial should also lead tochanges in the treatment of patients with stable CAD, with expected substantial healthcare savings.PCI has an established place in treating angina but is not superior to intensive medical therapy toprevent MI and death in symptomatic or asymptomatic patients, such as those enrolled in theCOURAGE trial. Secondary prevention has proved its worth, with lipid-modulating therapy, lifestylemodification, and the use of aspirin, beta-blockers, and ACE inhibitors. Patients who are clinicallyunstable, who have left main CAD, or in whom OMT has failed to control symptoms remaincandidates for revascularization. However, PCI should not play a major role as part of a secondaryprevention strategy.Case ConclusionSW has returned for her 6-month follow-up visit and reports "substantial improvement" in hersymptoms on an increased regimen of a beta-blocker, amlodipine, and ramipril. The nurse, followingstandard procedure in this primary care practice, had already "casually" asked her about heradherence to the doctors orders. Had she modified her diet? Was she taking all her medicines?Were there any of the medicines that she didnt like or thought caused her problems? When thephysician sees her, he questions her carefully about her symptoms and then asks her again abouther adherence to the treatment regimen. On the basis of her answers and what the nurse has toldhim, he believes that SW is being a relatively "good" patient. He can see, however, that her pain hasnot entirely resolved, and he expresses concern that her persistent symptoms may potentially requirerevascularization for full symptom relief. Her physician discusses the potential benefit and value ofcoronary revascularization, but the patient expresses a strong sentiment for a more conservativeapproach.SW was prescribed ranolazine 500 mg twice daily and, after 4 weeks of therapy, experienced asignificant improvement in her anginal symptoms. In view of her clinical response, both she and herphysician believed that her symptomatic improvement and quality of life were such that she shouldcontinue with this management approach.Conclusion
Not all patients will respond to medical therapy, as in the case above, so it is essential not to viewmedical therapy and myocardial revascularization as competing or mutually exclusive therapeuticapproaches. Clinical decision making must include a careful and thoughtful application of evidence-based data derived from clinical trials, but must also recognize and respect individual patientpreference, physician judgment and preference, and a synthesis of both subjective and objectiveparameters in configuring "the best approach" for a given patient. Both myocardial revascularizationand OMT have well-defined therapeutic roles, and the challenge providers face is integrating thisscientific information in a way that promotes the best individualized treatment that meets the needsand welfare of the patient.This activity is supported by an independent educational grant from Gilead.References 1. Maseri A, Crea F, Kaski JC, Davies G. Mechanisms and significance of cardiac ischemic pain. Prog Cardiovasc Dis. 1992;35:1-18. 2. Gibbons RJ, Abrams J, Chatterjee K, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). ACC/AHA 2002 guideline update for the management of patients with chronic stable angina -- summary article: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol. 2003;41:159-168. 3. Dunder K, Lind L, Lagerqvist B, Zethelius B, Vessby B, Lithell H. Cardiovascular risk factors for stable angina pectoris versus unheralded myocardial infarction. Am Heart J. 2004;147:502-508. 4. Hemingway H, Langenberg C, Damant J, et al. Prevalence of angina in women versus men: a systematic review and meta-analysis of international variations across 31 countries. Circulation. 2008;117:1526-1536. 5. Pocock S, Henderson R, Seed P, et al. Quality of life, employment status, and anginal symptoms after coronary angioplasty or bypass surgery. 3-year follow-up in the Randomized Intervention Treatment of Angina (RITA) Trial. Circulation. 1996;94:135-142. 6. Hemingway H, McCallum A, Shipley M, Manderbacka K, Martikainen P, Keskimaki I. Incidence and prognostic implications of stable angina pectoris among women and men. JAMA. 2006;295:1404-1411. 7. Buckley B, Murphy AW. Do patients with angina alone have a more benign prognosis than patients with a history of acute myocardial infarction, revascularisation or both? Findings from a community cohort study. Heart. 2009;95:461-467. 8. Lloyd-Jones D, Adams R, Carnethon M, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics -- 2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2009;119:e21-e181.
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effectiveness of percutaneous coronary intervention in optimally treated stable coronary patients. Circ Cardiovasc Qual Outcomes. 2008;1:12-20. 50. Weintraub WS, Spertus JA, Kolm P, et al; the COURAGE Trial Research Group. Effect of PCI on quality of life in patients with stable coronary disease. N Engl J Med. 2008;359:677-687.Authors and DisclosuresAs an organization accredited by the ACCME, MedscapeCME requires everyone who is in a positionto control the content of an education activity to disclose all relevant financial relationships with anycommercial interest. The ACCME defines "relevant financial relationships" as financial relationshipsin any amount, occurring within the past 12 months, including financial relationships of a spouse orlife partner, that could create a conflict of interest.MedscapeCME encourages Authors to identify investigational products or off-label uses of productsregulated by the US Food and Drug Administration, at first mention and where appropriate in thecontent.Author(s)William E. Boden, MD Professor and Associate Chair, Department of Medicine, SUNY Health Science Center, and Chief, Medical Service, VA Medical Center, Syracuse, N.Y. Disclosure: William E. Boden, MD, FACC, FAHA, has disclosed that he has received grants for clinical research from Abbott Laboratories, Merck & Co., Inc., Pfizer Inc., and sanofi-aventis. Dr. Boden has also disclosed that he served as an advisor or consultant for Abbott Laboratories, CV Therapeutics, and sanofi- aventis, and has served on the speakers bureau of Abbott Laboratories, CV Therapeutics, Merck & Co., Inc., Pfizer Inc., and sanofi-aventis.Writer(s)Linda Brookes, MScfreelance medical writer based in London and New YorkDisclosure: Linda Brookes, MSc, has disclosed no relevant financial relationships.Editor(s)Ariana Del NegroScientific Director, MedscapeCMEDisclosure: Ariana Del Negro has disclosed no relevant financial relationships.