Chronic stable angina is defined as angina that has remained. Chronic Stable Angina: Treatment and Follow-up CHRONIC STABLE ANGINA

Transcription

1 CHRONIC STABLE ANGINA Chronic Stable Angina: Treatment and Follow-up Case Study and Commentary, Paul R. Sutton, MD, PhD, and Stephan D. Fihn, MD, MPH INSTRUCTIONS The following article, Chronic Stable Angina: Treatment and Follow-up, is a continuing medical education (CME) article. To earn credit, read the article and complete the CME evaluation form on page 68. OBJECTIVES After participating in the CME activity, primary care physicians should be able to: 1. Identify the therapies that reduce mortality risk in patients with chronic stable angina versus those therapies that may reduce angina symptoms without affecting survival 2. Know the low-density lipoprotein (LDL) level at which cholesterol-lowering therapy should be initiated in persons with coronary artery disease and the optimal target LDL level 3. Understand the settings in which revascularization offers clear mortality benefit 4. Identify the issues that are important to review at followup visits 5. Recognize the features of progressive or unstable angina that warrant further evaluation or urgent hospitalization Chronic stable angina is defined as angina that has remained clinically unchanged for a period of 2 months or more. This article is the second of a 2-part series intended to review an evidence-based approach to the diagnosis and treatment of chronic stable angina. The first article, [1] published in last month s JCOM, presents an approach to diagnosis and risk stratification; the second part reviews treatment options and follow-up. Treatment choices for patients with chronic stable angina include lifestyle modification to reduce cardiovascular risk factors, pharmacologic therapy, and revascularization. Specific treatment recommendations are influenced by a patient s individual cardiovascular risk and comorbidities. The goals of therapy for patients with chronic stable angina are twofold: (1) to reduce the incidence of myocardial infarction (MI) and death (prolongation of life), and (2) to reduce the severity and frequency of anginal symptoms (improvement in quality of life). An algorithm for the treatment and followup of patients with suspected or confirmed stable coronary artery disease (CAD) is shown in the Figure [2 4]. CASE STUDY Initial Presentation In the first part of this series, a 55-year-old man with atypical angina presented to his primary care physician [1]. The patient s past medical history is notable for grade I hypertension, hypercholesterolemia controlled by diet, and mild asthma since childhood. He does not smoke, and his only medication is albuterol as needed. Based on age, sex, quality of pain, and cardiac risk factors, the pretest probability of significant CAD in this patient was estimated to be approximately 50% [1,5]. Given the intermediate probability of CAD, a diagnostic noninvasive stress test was performed. The patient exercised for 11 minutes on an exercise treadmill test and stopped due to shortness of breath. He had a normal hypertensive blood pressure response and 1.2 mm of downsloping ST-segment depression in leads V4 and V5 at peak exercise. Based on these results, his posttest probability of CAD was increased to only 68%, leaving some doubt regarding the diagnosis. Of greater importance, however, these results suggested a favorable prognosis, with a 1% risk of death during 4 years of follow-up [6]. Given the good prognosis, the physician deferred additional testing to confirm the diagnosis in favor of empiric treatment of probable CAD. What treatments are proven to reduce mortality in patients with probable or confirmed chronic stable angina? What treatments are effective in relieving symptoms of angina? Therapy to Reduce Mortality Risk Several interventions clearly reduce the risk of mortality in patients with chronic stable angina. Antiplatelet therapy, From the Veterans Affairs Puget Sound Health Care System and the Division of General Internal Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA. 52 JCOM June 2001 Vol. 8,. 6

2 CASE-BASED REVIEW Antianginal drug treatment Sublingual NTG History suggests vasospastic angina? (Prinzmetal) CHEST PAIN Intermediate to high probability of CAD High-risk CAD unlikely Risk stratification complete or not required Calcium channel blocker Long-acting nitrate therapy Education and risk factor modification Initiate educational program Medications or conditions that provoke or exacerbate angina? Treat appropriately Successful treatment? Aspirin 81 to 325 mg daily if no contraindication Serious adverse effect or contraindication Clopidogrel β-blocker therapy if no contraindication (especially if prior MI or other indication) Serious contraindication Successful treatment? Cigarette smoking? Cholesterol high? Smoking cessation program See NCEP guidelines [3] Add or substitute calcium channel blocker if no contraindication Serious contraindication Add long-lasting nitrate therapy if no contraindication Successful treatment? Successful treatment? Consider revascularization therapy Blood pressure high? Routine follow-up including (as appropriate) diet, exercise program, diabetes managment See JNC VI guidelines [4] Figure. Algorithm for the treatment and follow-up of patients with chronic stable angina or suspected angina. CAD = coronary artery disease; JNC = Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure; MI = myocardial infarction; NCEP = National Cholesterol Education Program; NTG = nitroglycerin. (Adapted with permission from Gibbons RJ, Chatterjee K, Daley J, et al. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina) [published erratum appears in J Am Coll Cardiol 1999;34:314]. J Am Coll Cardiol 1999;33: ) Vol. 8,. 6 June 2001 JCOM 53

3 CHRONIC STABLE ANGINA Table 1. Interventions for Treating Patients with Stable Coronary Disease Benefit/Intervention Prolong survival Aspirin or other antiplatelet therapy Smoking cessation Lipid-lowering therapy Antihypertensives ACE inhibitors Coronary artery bypass grafting Relieve angina β Blockers Calcium channel blockers Long-acting nitrates Short-acting nitroglycerin Coronary artery bypass grafting Percutaneous coronary intervention Of uncertain value Folate or B vitamins Hormone replacement therapy Moderate alcohol consumption Patient Subset All patients with chronic stable angina Patients who smoke cigarettes Patients with hypercholesterolemia Patients with hypertension Patients with known vascular disease or diabetes and 1 or more additional cardiac risk factors Patients with left main coronary stenosis or multivessel disease and diminished left ventricular function All patients with angina, barring contraindication Second-line choice for patients needing antianginal therapy Often used in combination with β blockers or calcium channel blockers Patients needing episodic relief of angina Patients with lifestyle-limiting angina despite maximum tolerated medical therapy Patients with 2- and 3-vessel CAD and coronary anatomy amenable to percutaneous intervention Patients with elevated homocysteine levels Postmenopausal women Uncertain benefits and potential risks of excessive consumption ACE = angiotensin-converting enzyme; CAD = coronary artery disease. treatment of hypercholesterolemia, treatment of hypertension, and smoking cessation have been shown by randomized controlled trial or by an overwhelming preponderance of observational data to save lives; these therapies should be priorities in caring for all patients with angina. Table 1 lists interventions that have been shown to improve survival or relieve symptoms in patients with stable angina. A consistent theme from studies of coronary risk factor reduction is that patients at highest risk derive the greatest absolute benefit. It is reasonable, therefore, to place special emphasis on interventions that improve survival in patients at intermediate and high risk. Antiplatelet Therapy All patients with angina should be treated with aspirin or another antiplatelet agent, barring contraindications. In randomized controlled trials, use of aspirin in patients with chronic stable angina reduced the relative risk of MI, stroke, or cardiovascular death by 33% [7,8]. This reduction in relative risk corresponds to an absolute risk reduction of approximately 5%; that is, 5 cardiovascular events would be saved for every 100 persons with known cardiovascular disease treated with aspirin for 6 months [8]. The improvement in survival apparently applies to patients with CAD and inadequately treated hypertension, as distinct from the uncertain benefit of aspirin in hypertensive patients without known CAD [8,9]. An average daily aspirin dose ranging from 75 to 325 mg is recommended and may be taken daily or on alternate days (typically 81 mg or 325 mg daily). In patients with a documented history of major gastrointestinal bleeding or known hypersensitivity to aspirin but who have a clear indication for antiplatelet therapy, clopidogrel or ticlopidine are reasonable alternatives. A single randomized controlled trial in patients with a history of MI, stroke, or peripheral vascular disease demonstrated that clopidogrel (75 mg daily) was effective in reducing the risk of MI, vascular death, and ischemic stroke [10]. Although ticlopidine effectively inhibits platelet activation and aggregation, it often causes side effects and has not been shown to reduce vascular events in patients with angina. Lipid-Lowering Therapy All patients with angina should be evaluated for hyperlipidemia with a fasting lipid panel. A virtually linear relationship exists between elevated cholesterol and risk of MI and cardiovascular death [11]. Elevations of low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol are independently associated with risk of MI and cardiovascular death [3]. Several randomized controlled trials have shown that lowering LDL cholesterol reduces cardiovascular events and/or improves survival in patients with CAD. In the 4S trial [12], use of hydroxymethylglutaryl-coareductase inhibitors (statins) in patients with known CAD and a markedly elevated cholesterol level (mean LDL cholesterol 54 JCOM June 2001 Vol. 8,. 6

4 CASE-BASED REVIEW Table 2. Commonly Used Lipid-Lowering Agents Category/Drug Dose Comments* HMG-CoA-reductase inhibitors (statins) Atorvastatin 10 to 80 mg daily Monitor patients with LFTs; elevated transaminases and risk of hepatitis are Cerivastatin 0.2 to 0.8 mg every night dose-related Fluvastatin 20 to 80 mg daily Myositis is a rare reaction Lovastatin 10 to 80 mg every night Dyspepsia, diarrhea, constipation, and flatulence are common side effects, Pravastatin 10 to 40 mg daily particularly early in therapy Simvastatin 5 to 80 mg every night Hepatitis and myositis occur more commonly when statins are coadministered with niacin or fibric acid derivatives Niacin Niacin 1.5 to 3 g daily in divided doses Monitor patients with LFTs Niacin SR 1 to 2 g 3 times daily Niacin may increase risk of myositis when administered with statins; may worsen hyperglycemia in diabetics; may worsen gout Flushing is common with niacin but is less common with the SR form Fibric acid derivatives Gemfibrozil 600 mg twice daily Monitor patients with LFTs Fenofibrate 67 to 200 mg daily Gemfibrozil reduces cardiovascular events in persons with low HDL and normal LDL These agents lower elevated triglycerides but have less effect on LDL These agents may increase risk of myositis when administered with statins and may be linked to cholelithiasis Cholesterol-binding resins Colestipol 2 to 16 g daily Bloating, abdominal pain, and constipation are often dose-limiting Cholestyramine 4 to 24 g daily HDL = high-density lipoprotein; HMG-CoA = hydroxymethylglutaryl-coenzyme A; LDL = low-density lipoprotein; LFT = liver function test; SR = sustained release. *Comments apply to all members of a drug category unless otherwise specified. was approximately 200 mg/dl, or 5.17 mmol/l) resulted in a 35% reduction in LDL cholesterol and an 8% increase in HDL cholesterol. This improved lipid profile was associated with a 3.7% reduction in absolute risk of mortality over 6 years of follow-up; in other words, 27 patients with known CAD and hypercholesterolemia would need to be treated for 6 years to prevent 1 death. The CARE [13] study demonstrated that use of statins reduced the rate of cardiovascular events in patients with CAD and more modestly elevated cholesterol. Of note, the decrease in coronary events was limited to the subgroup of patients with an initial LDL cholesterol level greater than 125 mg/dl (3.25 mmol/l). Recently, the fibric acid derivative gemfibrozil was shown to reduce the rate of nonfatal MI and coronary death in patients with known CAD, low HDL cholesterol (< 40 mg/dl, or 1.05 mmol/l), and normal or nearnormal LDL cholesterol (< 140 mg/dl, or 3.64 mmol/l) compared with placebo [14]. During 5 years of follow-up, the absolute risk reduction was 4.3%, which means that 23 persons would need to be treated for 5 years to prevent 1 MI or death from coronary causes. The major benefit observed was a reduction in nonfatal MI. There was no difference in the incidence of death from all causes. Recent guidelines from the National Cholesterol Education Program (NCEP) and the American Heart Association, American College of Cardiology, and the American College of Physicians American Society of Internal Medicine (AHA/ ACC/ACP-ASIM) recommend initiating therapy for a LDL cholesterol level greater than 130 mg/dl (3.38 mmol/l), with an optimal target of 100 mg/dl (2.59 mmol/l) [2,3]. Although a low-fat, low-cholesterol diet and moderate exercise are recommended, most patients will require pharmacologic therapy to achieve the target LDL. Choices of pharmacologic therapy include statins, niacin, and, in the setting of low HDL cholesterol or elevated triglycerides, fibric acid derivatives. Cholesterol-binding resins may augment other lipidlowering agents, but their use as monotherapy is often limited by gastrointestinal side effects. Table 2 lists commonly used lipid-lowering drugs. A reduced-fat diet and moderate aerobic exercise (walking 30 minutes or more, or a similar activity, 5 to 7 times a week) augment the success of pharmacotherapy for dyslipidemia and may be sufficient in patients near a desirable cholesterol level [3]. Exercise (and moderate alcohol use) increase HDL levels; this may be 1 reason why exercise exerts a Vol. 8,. 6 June 2001 JCOM 55

5 CHRONIC STABLE ANGINA Table 3. Commonly Used ACE Inhibitors and Angiotensin- Receptor Blockers Category/Drug Dose Comments ACE inhibitors Benazepril Captopril Enalapril Enalaprilat Fosinopril Lisinopril Moexipril Perindopril Quinapril Ramipril Trandolapril 5 40 mg daily mg 3 times daily mg daily mg IV every 6 hours mg daily mg daily mg daily 4 16 mg daily 5 80 mg daily mg daily 1 8 mg daily Angiotensin-receptor blockers Candesartan 2 32 mg daily Eprosartan mg daily Irbesartan mg daily Losartan mg daily Telmisartan mg daily Valsartan mg daily Cough occurs in as many as 20% of persons Angioedema is a rare but potentially life-threatening complication Closely monitor creatinine and potassium during initial therapy in persons with preexisting azotemia or at risk for renovascular disease Severe hypotension may occur, particularly early in treatment Doses may be divided twice daily These agents are contraindicated in pregnancy due to risk of birth defects These agents are not associated with cough; however, angioedema may occur Closely monitor creatinine and potassium during initial therapy in persons with preexisting azotemia or at risk for renovascular disease Severe hypotension may occur, particularly early in treatment te: ACE inhibitors have been shown to reduce mortality risk in patients with known vascular disease and other cardiovascular risk factors [18]. This same benefit has not been demonstrated for angiotensinreceptor blockers. ACE = angiotensin-converting enzyme; IV = intravenous. beneficial effect on cardiovascular risk. Recent studies concluded that pharmacologic therapy for persons with known CAD and hypercholesterolemia (secondary prevention) is both effective (increasing quality-adjusted years of life) and cost-effective for men and women of virtually all ages [15,16]. Antihypertensive Therapy All persons with angina should be evaluated for hypertension. Treatment of hypertension reduces cardiovascular events (principally stroke) and all-cause mortality. Among the many classes of antihypertensives, those with the best evidence for mortality reduction are β blockers and thiazide diuretics. Because β blockers are also effective at reducing symptoms of angina, they are the preferred first-line antihypertensive in patients with stable angina and hypertension. β Blockers are clearly indicated in patients with a history of MI. A structured overview of randomized controlled trials suggests that β-blocker therapy is associated with a 25% reduction in mortality in persons with a history of MI [17]. Long-acting calcium channel antagonists are also effective antihypertensive and antianginal medications. Evidence increasingly shows that subsets of patients at high-risk for cardiovascular events should be treated with angiotensin-converting enzyme (ACE) inhibitors. In the recently published HOPE study [18], patients with a history of CAD, diabetes, stroke, or peripheral vascular disease and at least 1 additional cardiovascular risk factor (hypertension, dyslipidemia, cigarette smoking, or microalbuminuria) were randomized to treatment with an ACE inhibitor or placebo and followed for an average of 4 years. In this study, total mortality was reduced by 1.8% (number needed to treat [NNT] of 56 for 4 years to prevent 1 death), and the primary outcome of MI, stroke, or cardiovascular death was reduced by 3.8% (NNT of 26 for 4 years to prevent 1 MI, stroke, or cardiovascular death). This study is striking for several reasons. First, it broadens the spectrum of patients with demonstrated benefit from treatment with ACE inhibitors. Previous studies had shown that persons with reduced left ventricular (LV) systolic function and subsets of patients with acute MI benefited from ACE inhibitors. This study extended the range of benefit to include persons at increased cardiovascular risk regardless of LV function. Second, the observed relative risk reduction ranged from 0.63 to 0.84 for a variety of cardiovascular outcomes and across all examined patient subsets, suggesting a robust result. Finally, the magnitude of benefit may have been greater than expected for the small observed average decrement in systolic and diastolic blood pressure (3 mm Hg and 2 mm Hg, respectively), suggesting that perhaps ACE inhibition confers benefits to patients at high cardiovascular risk in addition to providing antihypertensive effects [18]. Commonly used ACE inhibitors are listed in Table 3. Angiotensin-receptor blockers (ARBs) antagonize the action of angiotensin II, thereby reducing blood pressure. Although they are effective antihypertensives and are likely equivalent to ACE inhibitors in the treatment of patients with congestive heart failure, ARBs have not been shown to have any particular benefit in patients with CAD. Smoking Cessation All smokers should be vigorously encouraged to quit at each clinical encounter. Cigarette smoking is the leading cause of premature death in the United States [19]. Although the benefits of smoking cessation have not been directly demonstrated in patients with chronic stable angina, 2 lines of evidence support cessation. Three randomized controlled trials 56 JCOM June 2001 Vol. 8,. 6

6 CASE-BASED REVIEW in patients without known CAD demonstrated that quitting smoking reduced cardiac events by 7% to 47% [20 22]. Also, persons who continue to smoke after having a MI have a 22% to 47% greater risk of death [23]. Attributes of successful smoking cessation programs have been reviewed [24]. Both pharmacologic and nonpharmacologic approaches appear to be important [25]. Of note, consistent, direct reminders to stop smoking from physicians significantly increase smoking cessation [25,26]. Antianginal Therapy The therapies described above improve survival in persons with angina. Other pharmacologic therapies are used to treat the symptoms of angina but do not necessarily reduce mortality risk. The major classes of medications for the treatment of angina include β blockers, long-acting calcium channel blockers, and nitroglycerin/nitrates. Table 4. Commonly Used β Blockers Drug Selectivity Dose Comments Acebutolol β mg Has partial agonist twice daily activity Atenolol β mg daily Betaxolol β mg daily Bisoprolol β 1 10 mg daily Esmolol β µg/ IV β 1 -selective antagokg/min IV nist; has very short half-life (9.5 minutes) Labetalol ne mg Partial agonist activity; twice daily combined α and β blocker Metoprolol β mg twice daily Nadolol ne mg daily Pindolol ne mg Partial agonist activity 3 times daily Propranolol ne mg Relatively lipophilic, may twice daily cross the blood brain barrier Timolol ne 10 mg twice daily te. Potentially serious side effects common to all β blockers include bronchospasm, severe hypotension, congestive heart failure, and heart block. Common side effects include fatigue, dizziness, bradycardia, confusion, headache, and erectile dysfunction. IV = intravenous. β Blockers β Blockers exert their antianginal and anti-ischemic effects through the inhibition of cardiac and peripheral β-adrenergic receptors. β Blockade decreases heart rate, myocardial contractility, and blood pressure, resulting in decreased myocardial oxygen demand. β Blockers with partial β-adrenergic agonist activity, termed intrinsic sympathomimetic activity, have less effect on heart rate and blood pressure at rest. All β blockers appear to be effective for the treatment of chronic stable angina. Commonly used β blockers are listed in Table 4. β Blockers delay the onset of angina and increase exercise capacity in patients with exertional angina [27,28]. They are typically titrated to a dose necessary to reduce the resting heart rate to 55 to 60 bpm. In patients with more severe angina, heart rates less than 50 bpm may be well tolerated, provided they are not associated with symptoms of severe bradycardia or heart block. In patients with stable exertional angina, β blockers are typically adjusted to limit the exercise-induced heart rate to 75% or less of the threshold required to induce angina. β Blockers are contraindicated in the presence of severe bradycardia, high-degree atrioventricular block, sinus node dysfunction, and uncompensated congestive heart failure. Patients with severe peripheral vascular disease and claudication at rest may experience worsening of their symptoms. β Blockers should be used with caution in patients who have severe bronchospasm, although it is reasonable to attempt a trial with a low-dose β 1 -selective agent, such as metoprolol or atenolol. β Blockers are well tolerated in patients with diabetes, although they have the potential to mask symptoms of hypoglycemia. β Blockers are also contraindicated in the small subset of patients with pure variant or vasospastic angina (ie, angina occurring in the absence of fixed obstruction of the coronary arteries), in whom β blockade is unlikely to alleviate symptoms and may actually worsen angina due to unopposed α-adrenergic effects. As a result, calcium channel blockers are the preferred first-line agent in this group. Commonly reported side effects associated with β-blocker therapy include fatigue, asthenia, insomnia, worsening claudication, and erectile dysfunction. Calcium Channel Blockers Randomized controlled trials have demonstrated that calcium channel blockers and β blockers are equally effective in relieving angina and improving exercise tolerance [29,30]. Both dihydropyridine calcium channel blockers (eg, nifedipine, amlodipine, and felodipine) and nondihydropyridine agents (eg, verapamil and diltiazem) have been shown to be effective. Commonly used calcium channel blockers are listed in Table 5. All calcium channel blockers have some negative inotropic effect, although this effect varies significantly between classes of agents; verapamil and diltiazem typically have greater negative inotropic and chronotropic effect. Calcium channel blockers also reduce smooth muscle tone and result in coronary and peripheral vasodilation. Calcium channel blockers appear to exert their antianginal effects via Vol. 8,. 6 June 2001 JCOM 57

7 CHRONIC STABLE ANGINA Table 5. Commonly Used Calcium Antagonists Drug Dose Comments* Dihydropyridine Amlodipine 5 20 mg daily Common side effects include hypotension, peripheral edema, Felodipine 5 20 mg daily dizziness, flushing, nausea, and constipation Isradipine mg Reflex tachycardia may occur twice daily Amlodipine and felodipine may Nifedipine mg be used in patients with daily congestive heart failure Nitrendipine 20 mg daily or twice daily ndihydropyridine Diltiazem mg Side effects include hypotension, daily bradycardia, heart block, myocardial depression, heart failure, Verapamil mg constipation, and peripheral daily edema te: Only long-acting calcium channel blockers should be used in the treatment of patients with coronary artery disease. *Comments apply to all members of a drug category unless otherwise specified. improved coronary blood flow and diminished myocardial oxygen demand. Calcium channel blockers are the preferred first-line agent for treatment of patients with vasospastic or Prinzmetal s angina. Diltiazem and verapamil can reduce the heart rate by slowing atrioventricular conduction and are often used for rate control in patients with atrial fibrillation or flutter. Calcium channel blockers are contraindicated in the presence of decompensated congestive heart failure, although the newer vasoselective dihydropyridine agents amlodipine and felodipine are tolerated in patients with LV dysfunction [31]. ndihydropyridine calcium channel blockers (diltiazem and verapamil) exert a more prominent effect on myocardial contractility and conduction and should not be used in patients with severe bradycardia, high-degree heart block, and sinus node dysfunction. It is important to note that short-acting calcium channel antagonists such as immediateacting nifedipine, diltiazem, and verapamil have been associated with an increased risk of MI and excess mortality [32,33]. Although some controversy remains regarding the risk of short-acting calcium channel blockers, only longacting agents should be used for treating patients with chronic stable angina [2]. Peripheral edema and constipation are common side effects of all calcium channel blockers. Hypotension and worsening of congestive heart failure may also occur. Headaches, dizziness, and asthenia are commonly reported side effects. β Blockers clearly reduce mortality in patients with a history of MI [17]. In addition, they improve survival and reduce the risk of stroke and congestive heart failure in patients with a history of hypertension [34]. In persons with chronic stable angina without a history of MI or hypertension, however, it is unclear whether there is a significant difference in clinical outcomes between β blockers and long-acting calcium channel blockers. Analysis of several small randomized controlled trials comparing calcium channel blockers and β blockers have reported equivalent risks of death or MI, improvement in symptoms of angina, and increases in exercise time before onset of electrocardiographically detectable ischemia [35]. Combinations of β blockers and calcium channel antagonists relieve angina more effectively than either class of agent alone. β Blockers may blunt the reflex tachycardia that commonly occurs with the use of nifedipine, amlodipine, and felodipine. Caution should be used in combining diltiazem and verapamil with β blockers because of an increased risk of heart block or worsening of LV function. Nitrates/Nitroglycerin Nitrates and nitroglycerin are potent vasodilators that exert antianginal effects by improving coronary blood flow and reducing myocardial oxygen demand. These agents dilate epicardial coronary arteries, which directly improves myocardial perfusion; they also increase venous capacitance, which reduces myocardial oxygen demand. The decreased oxygen demand reduces preload and arterial blood pressure, which often results in a reflexive increase in sympathetic tone and thus an increased heart rate. Therefore, longacting nitrates are often used in combination with negative chronotropic agents such as β blockers or calcium channel blockers in the treatment of chronic stable angina. Combinations of antianginal medications are more effective at relieving angina than are single drugs. Short-acting nitroglycerin tablets or spray is appropriate for the immediate relief of exercise-induced or rest angina. They may also be used to avoid angina when taken several minutes prior to expected exertion. Long-acting nitrate preparations, in tablet, ointment, or patch form, are effective for the treatment of chronic stable angina. Commonly used nitroglycerin and nitrate preparations are listed in Table 6. Nitroglycerin and nitrates should not be administered to patients who are taking sildenafil (Viagra) because of the potential risk for life-threatening hypotension [36]. Nitroglycerin and nitrates are relatively contraindicated in patients with severe aortic stenosis or hypertrophic obstructive cardiomyopathy because of an increased risk of syncope. The reduction in preload may reduce cardiac output in patients with severe aortic stenosis. In patients with hypertrophic obstructive cardiomyopathy, reduced preload and LV volume may increase the degree of LV outflow tract obstruction. A major issue associated with the long-term use of nitroglycerin 58 JCOM June 2001 Vol. 8,. 6

8 CASE-BASED REVIEW and nitrates is the development of tachyphylaxis, which develops via an unclear mechanism. It is important to include an adequate nitrate-free period (8 to 12 hours each day) to minimize the impact of nitrate tolerance. Headaches are a common and often limiting side-effect of nitroglycerin and nitrate therapy. Headaches will diminish with continued use of nitrates in up to 80% of patients. What factors must be considered when treating angina in patients with diabetes? Persons with diabetes mellitus and angina merit special consideration in terms of pharmacologic therapy. They are at particularly high risk for MI and cardiovascular death. Results of a recent cohort study suggest that middle-aged persons with diabetes without a prior history of MI have a risk for MI and coronary death equivalent to that of nondiabetic patients with a history of prior MI [37]. Accordingly, it is important to aggressively treat cardiovascular risk factors, especially elevated blood pressure, in persons with diabetes. Results of the recent UKPDS [38] and HOPE [39] studies emphasize the importance of antihypertensive treatment in these patients. The UKPDS study suggests that β blockers and ACE inhibitors are equally effective in reducing rates of cardiovascular events [38]. The HOPE study substantiates the mortality benefit of ACE inhibitors in persons with diabetes and 1 or more additional cardiovascular risk factors, even in persons who are normotensive [39]. In the FACET study [40], persons with type 2 diabetes and hypertension were randomized to receive an ACE inhibitor versus a dihydropyridine calcium channel blocker. Both agents were effective at reducing blood pressure, but cardiovascular events were less common in patients treated with the ACE inhibitor. Although it remains uncertain whether this result is due to increased cardiovascular risk with amlodipine or reduced cardiovascular risk with fosinopril, most experts consider calcium channel blockers as third-line agents in patients with diabetes and hypertension. The HOT [41] study supports aggressive blood pressure reduction, to a target blood pressure of 135/80 mm Hg or lower, in persons with diabetes. When to initiate antiplatelet therapy in diabetic persons remains uncertain; however, it is reasonable to treat persons with diabetes and any additional cardiovascular risk factor with aspirin or equivalent antiplatelet therapy [42]. The American Diabetes Association recommends a target LDL cholesterol level of 100 mg/dl (2.59 mmol/l) [43]. Interestingly, while hyperglycemia and hyperinsulinemia are felt to be pathogenic in the development of atheromatous plaques, randomized controlled trials of intensive blood glucose control in persons with either type 1 or type 2 diabetes Table 6. Commonly Used Nitroglycerin and Nitrate Preparations Drug Dose Duration of Effect Nitroglycerin Sublingual mg minutes Spray 0.4 mg minutes Transdermal mg/hr 8 12 hours every 12 hours Nitrates Isosorbide 5 80 mg Up to 8 hours dinitrate 2 3 times daily Isosorbide 20 mg twice daily hours mononitrate mg daily* te: Common side effects include hypotension, dizziness, and headache. Syncope may occur in persons with aortic stenosis. Nitroglycerin and nitrates are contraindicated in persons taking sildenafil (Viagra) due to risk of life-threatening hypotension. *Extended-release formulation. have not demonstrated a corresponding reduction in cardiovascular endpoints [44 46]. Based on available data, the greatest reduction in cardiovascular risk in persons with diabetes may be accomplished by aggressive treatment of traditional cardiovascular risk factors. When should revascularization be recommended in patients with chronic stable angina? Coronary Artery Bypass Graft and Percutaneous Coronary Intervention Coronary revascularization is effective at reducing symptoms of angina and improves survival in subsets of patients with CAD. Revascularization may be performed surgically (coronary artery bypass graft [CABG]) or angiographically, with or without intracoronary stents (percutaneous coronary intervention [PCI]). CABG offers improved survival in selected patients [47]. A recent study conducted a systematic overview of randomized trials of CABG versus medical management. The mortality rate in patients with left main coronary stenoses or multivessel CAD and reduced LV function randomized to CABG was more than 5% lower at 5 years (10.2% versus 15.8%) and 4% lower at 10 years (26.4% versus 30.5%) compared with the medical management group [48]. While this overview also concluded that persons with proximal stenoses of the left anterior descending (LAD) coronary artery and normal LV function enjoyed a significant mortality benefit from surgery, the recent MASS trial [49] found equivalent survival in patients with LAD stenoses randomized to CABG, PCI, or medical management. After Vol. 8,. 6 June 2001 JCOM 59

9 CHRONIC STABLE ANGINA 5 years of follow-up, mortality (and risk of MI) was equivalent in all groups. Thus, it appears that only a relatively small subset of patients with CAD have a clear survival advantage following CABG. That said, CABG is effective at relieving symptoms of angina and is certainly a reasonable choice in patients who continue to have intolerable symptoms of angina despite adequate medical management, even without clear mortality benefit [2]. Since its introduction in the 1970s, PCI has been increasingly used as an early treatment for patients with angina. PCI has the advantages of relatively low morbidity and mortality, short hospital stay, and rapid improvement in symptoms. On the other hand, not all stenotic lesions are amenable to PCI, and there is a risk of acute coronary occlusion necessitating salvage CABG. The need for early restenosis of successfully treated lesions remains an important problem, although the introduction of intracoronary stents and recent advances in periprocedure pharmacologic therapies have greatly reduced this risk. Randomized trials comparing PCI and medical management in 1- and 2-vessel CAD and normal LV function have demonstrated equivalent survival in the 2 groups. Patients treated with PCI were more likely to be angina-free at 6 months of follow-up [50], although they often required repeat interventions [51]. Caution regarding the use of PCI in persons with low-risk CAD is warranted. In the recently published RITA-2 study [51], patients with 1- or 2-vessel CAD and normal LV function randomized to PCI had an increased risk of cardiac death and acute MI after 2.7 years of follow-up; however, it has been pointed out that existing evidence is from studies that employed older PCI techniques. Whether current optimal PCI techniques (ie, employing intracoronary stents, glycoprotein IIb/IIIa platelet inhibitors, and antithrombin agents) will prove to be superior to optimal medical management remains to be seen. Two randomized trials sponsored by the National Heart, Lung, and Blood Institute are currently underway to address this question (SOCRATES and COURAGE). Two recent trials have compared PCI with CABG for patients with 2- and 3-vessel CAD and normal LV function [52 55]. In both trials, lesions amenable to PCI were required for inclusion, so these studies represent a small subset of patients with angina. Overall, survival in both groups was equivalent. In the BARI trial [55], but not the EAST trial [54], persons with diabetes had higher short- and long-term mortality when treated with PCI compared with CABG [54,55]. Relief of angina was superior in the CABG group, and more than half of patients assigned to PCI required additional revascularization procedures during 5 years of follow-up. On the other hand, initial costs and short-term mortality were higher in the groups randomized to CABG [56]. Based on available data, medical management and revascularization offer equivalent survival in most instances. In the absence of left main disease or multiple-vessel CAD and diminished LV function, decisions between medical management, PCI, and surgical revascularization should be based largely on patients preferences and the expertise available locally. It is appropriate for primary care physicians to initiate a discussion of the estimates of an individual patient s average annualized mortality risk, the risk of revascularization procedures, likelihood of symptom reduction, and requirement for additional antianginal medications. When possible, estimates of risk should be based on actual local experience rather than optimal results drawn from the literature. What changes in lifestyle are recommended for patients with chronic stable angina? What therapies purported to reduce risk in angina patients remain of uncertain benefit? Diet and Exercise As mentioned above, smoking cessation improves survival and should be advocated at every clinical encounter. Diet modification and regular aerobic exercise are also important elements of a multifactorial approach to cardiac risk reduction. Although studies of the effect of diet therapy for patients with CAD have not consistently shown a benefit [2], dietary modification is likely to impact several well-defined cardiac risk factors, including hypertension, dyslipidemias, diabetes mellitus, and obesity. It is prudent for persons with CAD to follow a diet low in cholesterol and fat, particularly saturated fats. Consumption of ample quantities of fresh fruits and vegetables and replacement of saturated fats with monounsaturated oils (eg, olive oil) are particularly desirable. Recently, a study of this so-called Mediterranean diet in persons with a history of MI showed a significant reduction in death and nonfatal MI [57], but the results of this study have not been confirmed. Patients with chronic stable angina should be encouraged to incorporate at least moderate aerobic physical activity in their daily lives. Moderate physical activity consists of walking briskly for 30 minutes or more, 5 to 7 times a week. Several randomized trials of the effects of regular aerobic exercise in patients with chronic stable angina have demonstrated improvements in symptoms or markers of myocardial ischemia. Regular exercise is safe in cardiac rehabilitation following CABG; it is inferred to be safe in chronic stable angina [2]. In patients with CAD who have been previously sedentary, it is reasonable to perform a noninvasive stress test, such as exercise treadmill testing, prior to initiating a moderate or vigorous exercise program [58]. 60 JCOM June 2001 Vol. 8,. 6

10 CASE-BASED REVIEW Treatment of Uncertain Benefit Several types of treatment are of unproved benefit in persons with chronic stable angina. Perhaps most controversial at the present time is the use of hormone replacement therapy in postmenopausal women. Observational studies have consistently associated estrogen use with reduced cardiac risk. The sole published randomized trial of hormone replacement therapy in women with known CAD, however, did not show a reduction in cardiovascular events over 4 years of follow-up [59]. There was a small but statistically significant increase in thromboembolic events during the first year of the study. A recent prepublication press release from the Women s Health Initiative reported an excess of cardiovascular events in women randomized to hormone replacement [60]. In view of these results from clinical trials, hormone replacement is not recommended for purposes of reducing cardiovascular risk [61], although this therapy clearly offers other benefits in postmenopausal women. Antioxidant vitamins (vitamin C, vitamin E, and β-carotene) are sometimes recommended to persons with chronic stable angina because of the hypothesized role of oxidation of LDL in the development of atherosclerosis; however, the preponderance of data do not support this practice. A Finnish study [62] of smokers treated with β-carotene or vitamin E failed to show a reduction in cardiac risk. The recent HOPE study [39] also showed no benefit for treatment with vitamin E. Vitamin C in patients with CAD has not been evaluated in a clinical trial. Increased serum homocysteine is an independent risk factor for CAD, peripheral vascular disease, and cerebrovascular disease [63]. Hyperhomocystinemia is commonly caused by nutritional deficiencies of vitamins B 6, B 12, and folate [64]. Vitamin supplementation usually lowers elevated homocysteine levels and is relatively inexpensive, but whether such treatment is beneficial remains to be determined. Similarly, elevated lipoprotein(a) [Lp(a)] levels are linked to ischemic heart disease risk. Elevated Lp(a) levels are found in 15% to 20% of persons with premature CAD [65]. Lp(a) levels are largely determined genetically, and only niacin, among commonly used lipid-lowering drugs, has any effect on Lp(a) levels. It is not known whether lowering Lp(a) levels reduces cardiac risk. Other putative risk factors for CAD such as ferritin (a marker of iron load and/or inflammation), history of chlamydial infection, aggressive personality styles, and ingestion of coffee have been proposed based on epidemiologic studies. These proposed associations have not been substantiated, and there is no good evidence that treating these conditions reduces cardiovascular risk. It is fair to conclude that any relationship between these putative risk factors and the development of CAD is weak, whereas the benefit of treating known cardiovascular risk factors has been well demonstrated. Initiation of Therapy The physician prescribes daily aspirin at a dose of 325 mg. Results from a fasting lipid panel are notable for a LDL cholesterol level of 145 mg/dl and HDL of 40 mg/dl. As a result, the patient is started on simvastatin 20 mg each night with a target LDL cholesterol of 100 mg/dl [3]. The physician decides to initiate treatment of the patient s hypertension and angina with a single agent. Because of the patient s history of asthma, a case may be made for avoiding β blockers altogether; however, his asthma is mild and he has no history of hospitalizations or steroid use. He is started on metoprolol, a β 1 -selective agent, at a low dose of 25 mg twice daily. The physician also prescribes nitroglycerin tablets and instructs the patient in their use: In the event of chest pain, sit down, take mg tablet sublingually every 5 minutes until the pain is relieved; call for emergency medical assistance if no relief is obtained after 3 tablets. The physician recommends that the patient begin a graded moderate exercise program with a target of 30 minutes of brisk walking (symptom-limited) each day and that he eat a diet emphasizing saturated or monounsaturated fats and oils, fresh fruits, and vegetables, obtaining less than 30% of his calories from fat. In discussion with the patient, a consultation with a clinical dietitian is obtained to assist with meal planning. Followup is scheduled in 3 months or sooner if warranted by changes in anginal symptoms. What are important elements of routine follow-up of patients with chronic stable angina? When are repeat risk stratification and hospitalization necessary? Approach to Follow-up Angina symptoms, medication use, and modifiable cardiac risk factors should be addressed in regular follow-up visits for patients with chronic stable angina. The optimal frequency of periodic follow-up is uncertain but is influenced by the patient s clinical stability and the establishment of consistent communication with the patient and other providers involved in the care of the patient. It is reasonable to schedule follow-up visits every 3 to 6 months in the first year following a confirmed or probable diagnosis of CAD. The visit interval may increase over time in selected patients who are both clinically stable and who may be relied upon to call or make an appointment with new or changing symptoms. History Anginal symptoms should be reviewed at each visit. Changes in clinical status may result from progression of Vol. 8,. 6 June 2001 JCOM 61

11 CHRONIC STABLE ANGINA Table 7. Canadian Cardiovascular Society Classification (CCSC) for Grading Angina Pectoris Class I Ordinary physical activity does not cause angina, such as walking, climbing stairs. Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation. Class II Slight limitation of ordinary activity. Angina occurs on walking or climbing stairs rapidly, walking uphill, walking or stair climbing after meals, walking in cold or wind, under emotional stress, or only during the few hours after awakening. Angina occurs on walking more than 2 blocks on the level and climbing more than 1 flight of ordinary stairs at a normal pace and in normal conditions. Class III Marked limitations of ordinary physical activity. Angina occurs on walking 1 or 2 blocks on the level and climbing 1 flight of stairs in normal conditions and at a normal pace. Class IV Inability to carry on any physical activity without discomfort; anginal symptoms may be present at rest. Adapted with permission from Campeau L. Grading angina pectoris [letter]. Circulation 1976;54:522. CAD, but also may result from changes in comorbid conditions, medication side effects, noncompliance with recommended pharmacotherapy, and changes in social factors. A thorough follow-up history may be obtained by asking 6 questions: 1. Have the patient s anginal symptoms increased in frequency or become more severe since the last visit? When assessing for symptom changes, it is important to quantify exercise tolerance using consistent measures for the patient (eg, angina occurs following how many flights of stairs?) and to inquire about changes in nitroglycerin use. Angina severity should be graded according to the Canadian Cardiovascular Society Classification (Table 7) [66]. 2. Has the patient decreased his or her level of physical activity since the last visit? This is an important question because some patients may reduce their level of activity to avoid worsening angina. 3. How well is the patient tolerating therapy? Ascertain whether there are any new symptoms or signs potentially attributable to medications. Examples include increased lower extremity edema as a consequence of calcium channel blockers or the development of wheezing after the introduction of β-blocker therapy. 4. How successful has the patient been in modifying risk factors and improving knowledge about ischemic heart disease? Patients should always be asked if they have quit smoking and if they understand the importance of treating blood pressure. Efforts to educate patients and help them manage their chronic stable angina require frequent reminders, repetition, and reinforcement. 5. Has the patient developed any new comorbid illnesses or has the severity of treatment of known comorbid illnesses worsened the patient s angina? Examples of comorbid illnesses that may directly impact angina include congestive heart failure, hypertension, aortic stenosis, pulmonary disease, anemia, and hyperthyroidism. Given the importance of LV dysfunction in predicting mortality, it is particularly important to inquire about signs such as weight gain or edema and symptoms such as orthopnea or dyspnea on exertion. 6. Have any new social factors developed that impact anginal symptoms? Changes in social factors, such as an ill spouse, financial stressors, or homelessness, may affect the ability of patients to care for themselves. Physical Examination and Laboratory Testing Patients should be examined at each visit. Although the details of the examination are appropriately influenced by changes in clinical status, certain elements should be consistently reviewed [2]. Vital signs should be obtained at each visit, including blood pressure, heart rate and rhythm, and weight. It is important to assess for the presence of crackles, wheezes, rhonchi, or reduced breath sounds, signs of chronic lungs diseases or congestive heart failure. Treatment of pulmonary conditions, such as chronic obstructive pulmonary disease, may be required to reduce symptoms of angina; the presence of signs of congestive heart failure may indicate progression of the underlying CAD. The cardiac examination should include auscultation for the presence of arrhythmias, new or changed murmurs, gallops, and changes in the location, intensity, or duration of the apical impulse. Given the importance of LV dysfunction in predicting mortality in patients with chronic stable angina, it is important to evaluate for systemic signs of volume overload: elevated jugular venous pulsation, hepatomegaly, hepatojugular reflux, and peripheral edema. Routine laboratory testing is determined largely by an individual patient s comorbidities and treatment regimen. For example, annual measurement of glycosylated hemoglobin and assessment for proteinuria are recommended for persons with diabetes. It is recommended that patients started on lipid-lowering therapy have follow-up fasting lipid panels and liver function testing 8 to 12 weeks following initiation of therapy and periodically thereafter [3]. Myositis is a rare complication of statin therapy; routine measurement 62 JCOM June 2001 Vol. 8,. 6