Medical Management of Stable Angina and Unstable Angina in the Elderly With Coronary Artery Disease

CORONARY ARTERY DISEASE IN THE ELDERLY

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MEDICAL MANAGEMENT OF STABLE ANGINA AND UNSTABLE ANGINA IN THE ELDERLY WITH CORONARY ARTERY DISEASE Harold G. Olson, MD, a n d Wilbert S. Aronow, MD

Coronary artery disease is a major clinical problem in the elderly. Approximately half of all deaths of persons older than 65 years of age are the result of coronary artery disease, and of all coronary deaths, 80% occur in patients 65 years ' , ~ ~ show that an old or recent myocardial infarction can of age or ~ l d e r . ~Studies be found in 10% of hearts at autopsy of persons 65 years of age or ~ l d e r .The ~~,~~ prevalence of significant coronary disease is estimated at 20% in the elderly.71 Angina pectoris is the initial symptom of coronary artery disease in more than 80% of elderly patients, but in many of these patients angina pectoris is atypical.69 Instead of chest pain, the elderly patient may complain of dyspnea on exertion, excessive fatigue, palpitations, excessive sweating, dizziness, and even syncope as part of his or her angina syndrome. Compared to the younger patient with coronary artery disease, the elderly patient with coronary artery disease tends to have more multivessel coronary artery disease and left ventricular dysfunction. Moreover, data from the Coronary Artery Surgery Study (CASS)36showed that the elderly had more hypertension, cerebral vascular disease, diabetes, and congestive heart failure than did younger patients. GENERALMEASURES

After the diagnosis of coronary artery disease is established in the elderly patient, one should identify and correct reversible factors that could aggravate

From the Department of Medicine, University of California, Irvine, College of Medicine, Irvine; Coronary Care Unit, Long Beach VA Medical Center, Long Beach, California (HGO); and the Mount Sinai School of Medicine and Hebrew Hospital Home, Bronx, New York (WSA)

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myocardial ischemia and its main clinical manifestations including angina pectoris. These potentially reversible factors include anemia, hyperthyroidism, obesity, uncontrolled hypertension, uncorrected valvular heart disease such as aortic stenosis, arrhythmias such a s atrial fibrillation, and congestive heart failure. In addition, traditional coronary risk factors should be identified and modified if possible. Smoking should be totally discontinued. Studies indicate that even in the elderly, smoking cessation improves prognosis." Hyperlipemia should be diagnosed and treated with either diet or drug therapy or both. Recent lipid-lowering trials have shown that patients treated aggressively with lipid-lowering drugs have an approximately 40% reduction in cardiac events (death, myocardial infarction, unstable angina, or need for bypass surgery at follow-up) compared to patients who are treated with less intensive drug-lowering therapy.'0,'5Whether these data on lipid lowering can be applied to the elderly population with coronary artery disease requires further study. Nevertheless, a reasonable goal for lipid management in the elderly patient with established coronary artery disease should be to lower the total cholesterol to less than 200 mg/dL and the low-density lipoprotein (LDL) levels to less than 100 mg/dL, while maintaining the high-density lipoprotein (HDL) levels greater than 40 mg/dL. If this cannot be achieved by diet alone, drug therapy should be considered.' All elderly patients with angina should be maintained on daily aspirin therapy (180 to 325 mg/d). Carefully controlled studies have shown that at follow-up patients receiving long-term aspirin therapy had a decreased incidence of myocarAlso, , ~ ~ whenever dial infarction and stroke versus patients receiving p l a ~ e b o . ' ~ possible, patients should be encouraged to engage in some form of exercise program. Studies show that elderly patients with coronary artery disease who undergo an exercise program experience an improvement in exercise performance and psychosocial ~ e l l - b e i n g . ~ ~ DRUG THERAPY

Before undertaking drug therapy, consider that multiple host factors exist in the elderly that make drug treatment problematic. First, drug absorption may be erratic because of gastrointestinal motility problems that are ubiquitous in the elderly. Second, drug distribution may be underestimated because of decreased lean body mass. Third, hepatic and renal dysfunction that may be present in the elderly could alter the metabolism and excretion of drugs. Fourth, elderly patients tend to have increased sensitivity to drugs independent of dmg absorption and drug pharmacokinetics. Fifth, elderly patients commonly take many drugs at a time, resulting in a n increased possibility of significant drug interaction^.^^ Accordingly, to prevent an adverse drug reaction from antianginal drug therapy in the elderly, follow the old clinical axiom, "start low and go slow." The fundamental goal of antianginal drug therapy is to relieve or prevent myocardial ischemia manifested clinically as angina. Myocardial ischemia occurs when the myo.-z:..A:z? . :.,77cc> ,--* A z --.--.-. 2z.2 c..,.-aa.42 +h* ????~C92?.Ai21 .~??????I?T h.e ?l?ccec -, .J -,.----.---I - C..,?7ZS?? -.., .T -. - th?.ee of antianginal agents (nitrates, beta-blockers, and calcium-entry blockers) favorably alter either myocardial oxygen demand, myocardial oxygen supply, or both so that the threshold for development of myocardial ischemia is changed. These drugs allow the coronary patient to perform at a higher level of activity before myocardial ischemia and hence angina occurs, and in the case of rapid-acting antianginal agents like nitroglycerin, ongoing myocardial ischemia can be abruptly terminated. We now review the three classes of antianginal drugs: the nitrates, the beta-blockers, and the calcium-entry blockers. LuA-AwA

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Nitrates

Nitrates have been used for more than a century in the treatment of angina pectoris after amyl nitrate was shown to abort an angina attack in a patient.16 These remarkable compounds have been proven both safe and effective; use of nitrates is the cornerstone in drug treatment of angina pectoris. The mechanisms of action of the nitrates have been studied extensively. All organic nitrates share a common effect; they are vasodilators. They dilate veins, arteries, and arterioles throughout the body. After their entry into the blood stream, nitrates enter vascular smooth muscle where they undergo chemical conversions known as denitration reactions.45With the requirement of sulfhydryl groups from intracellular cysteine compounds, the NO, side chain of the nitrate compound is converted to nitric 5h Nitric oxide activates intracellular oxide (NO) or a nitrosothiol derivati~e.~'. soluble guanylate cyclase which converts quanosine triphosphate (GTP) to cyclic quanosine monophosphate (cGMP). Increased intracellular levels of cGMP facilitate the phosphorylation of a protein kinase that triggers a fall in cytosolic calcium and relaxation of the vascular smooth muscle. Fortuitously, the active metabolite of the nitrates is NO-the same compound ascribed to endothelial derived relaxing factor (EDRF). Recent studies have shown that the vascular endothelium is a virtual factory that produces various vasodilators, vasoconstrictors, anti- and pro-thrombotic factors, and anti- and pro-growth factors in response to physiologic stimuli.25For example, increased shear stress from flowing blood stimulates the endothelium to produce and release EDRF, which in turn relaxes vascular smooth muscle by the mechanisms described above.25Studies have shown that the endothelium of vessels with atherosclerosis is dysfunctional, resulting in attenuated EDRF activity. This abnormally can even be present in patients without overt coronary artery The net disease but with coronary risk factors such as hyperchole~terolemia.~~ effect of reduced EDRF activity is that coronary vasoconstriction is favored over coronary vasodilation and that stimuli that would normally induce coronary vasodilation (such as exercise) may paradoxically produce coronary vasoconstrict i ~ n Thus, . ~ ~ the exogenous administration of organic nitrates to patients with coronary artery disease seems to make good sense because nitrates may in part replace the endothelial NO deficiency that is a major aberration produced by the atherosclerotic disease process. Finally, nitrates may have an antiplatelet effect, which should benefit the patient with coronary artery disease by decreasing the risk of thrombosis and progression of coronary artery lesions.z6 The mechanisms whereby the nitrates act to relieve or prevent myocardial ischemia include: (1) reduction in myocardial oxygen demand (MVo,) and (2) increase in myocardial oxygen supply. Nitrates reduce MVo, by decreasing myocardial wall tension, a major determinant of MVO,.~~ The other two major determinants of MVo, are heart rate and myocardial contractility. Wall tension is determined by intracardiac volume times systolic blood pressure. The nitrate by its peripheral dilatory action on venous capacitance vessels causes a redistribution of blood volume toward the splanchnic and mesenteric circulations. This results in a decrease in venous return and a reduction in intracardiac volume.38 The combined effect of nitrate's vasodilatory action on both veins and arterioles results in reduction of systolic blood pressure. Thus, the net effect of nitrate's vasodilatory action is to reduce myocardial wall tension. With the drop in blood pressure occurring after administration of nitrates, a compensatory increase in heart rate may occur that would tend to increase MVo,. However, the marked drop in myocardial wall tension induced by nitrates generally outweighs any increase in heart rate, so that the net effect is an overall reduction in MVo,.

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Nitrates increase myocardial oxygen supply by vasodilating epicardial coronary arteries and collateral coronary vessel^.'^,'^ Nitrates also have a small vasodilator effect on prearteriolar coronary resistance vessels. Additionally, by reducing ventricular volumes by their action on venous capacitance vessels, nitrates lower left ventricular diastolic pressure. This results in a wider aortic-left ventricular diastolic pressure gradient, thus a greater driving pressure is available for coronary flow to occur during diastole. Moreover, the reduction of left ventricular enddiastolic pressure lessons diastolic compression on the intramyocardial vessels that supply the subendocardium. The net effect of this action is the improvement of myocardial blood flow to the subendocardium, the region of the heart most susceptible to myocardial i~chemia.~ Nitrates are generally well tolerated and safe. The major contraindications for nitrate usage-are severe hypotension, increased intracranial pressure, and known hypersensitivity to nitrates. The major side effects of nitrates are hypotension and headaches. Hypotension is the result of the nitrate's reduction of preload and afterload. It may occur within minutes after sublingual administration of nitroglycerin and 30 minutes to 1 or 2 hours after oral ingestion of long-acting nitrate. The symptoms may range from dizziness to syncope. Hypotension is most likely after initial dosing, with high doses of nitrates, with upright posture, with hypovolemia (for example, with diuretic usage), with autonomic dysfunction, or with concomitant vasodilator usage (calcium entry blockers, angiotensionconverting enzyme inhibitors and other antihypertensive agents). Elderly patients are particularly susceptible to hypotension from nitrates because they generally have some degree of diastolic ventricular dysfunction, which makes them preload sensitive, and they may have a blunted baroreceptor response to a sudden lowering If symptomatic hypotension occurs, treatment consists of lying of blood pre~sure.~' the patient down with or without elevation of the legs. Blood pressure usually returns to baseline and no further therapy is necessary. A rare form of neurocardiogenic syncope may occur after nitrate ingestion particularly in patients with acute ischemic syndromes. In these patients hypotension is usually associated with bradycardia similar to a typical vasovagal syncope. Treatment of this rare form of nitrate syncope includes laying the patient down, elevating the legs, and administering fluids and atropine as necessary. To avoid nitrate-induced hypotension, start with the lowest dose of nitrates and titrate the dose upward slowly until clinical efficacy is achieved. Patients should be instructed to lie down at the first sign of light headedness. Nitrate headache is a vexing and almost intractable problem. The headache may range from a mild frontal headache to a generally throbbing headache involving the head and neck and associated with nausea and vomiting. In the coronary care unit (CCU),wherein the majority of patients receive intravenous nitroglycerin, we have coined the term "CCU migraine." The most likely mechanism for the headache is nitrate-induced vasodilation of extracranial and intracranial arteries.53 At least 50% of patients exposed to nitrate therapy develop some form of headache. An important clinical impact of the nitrate headache is that once a patient has a severe headache aiter nitrate ingesiiurl i ~ ULe she wiIi iiot warkt to take any ?xiher nitrates, including sublingual nitroglycerin (TNG). Thus, the seriousness of this side effect must be recognized and minimized accordingly. The best approach is to use the lowest dose of nitrates possible and titrate slowly upward if necessary for clinical efficacy. If the patient develops a nitrate headache the dose should be reduced, but maintain therapy while giving an analgesic such as Tylenol, aspirin, or Tylenol and codeine. If continuous nitrate treatment can be maintained for a week or 10 days, headaches generally decrease in severity or go away altogether because of the development of nitrate tolerance. To maintain nitrate therapy

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throughout this critical week while tolerance to the nitrate is occurring requires all the skills that a physician has at his disposal. Studies have shown that continuous exposure to nitrates may result in some degree of nitrate tolerance. These include studies using 24-hour nitroglycerin infusion, transdermal nitroglycerin patches, regimens of isosorbide dinitrate administration 4 times a day, and long-acting sustained-released nitrate prepara-ti on^.^' The clinical impact on nitrate tolerance is, however, unknown. With the onset of tolerance the patient may notice that a single 0.4-mg dose of sublingual nitroglycerin does not abort a typical angina attack. The patient should increase the dose of nitroglycerin to regain its effect. The mechanism for nitrate tolerance is most likely multifactorial and includes: (1) depletion of sulfhydry1 groups, which are needed for the conversion of nitrates to NO; (2) activation of various counterregulatory neurohormones such as catecholamines, arginine vasopressin, plasma renin, aldosterone, and angiotension, which result in vasoconstriction and fluid retention; and (3) increased intravascular blood volume.27 Most studies suggest that to prevent nitrate tolerance, continuous nitrate dosing with long-acting nitrates should be avoided. During a given 24-hour period, a 12- to 14-hour nitrate-free interval should be established. For example, a twice a day or 3 times a day administration of oral isosorbide dinitrate is less likely to be associated with tolerance compared to a 4 times a day dosing.57Nitroglycerin patches should be applied for 12 hours and taken off at night or vice versa.24The determination of the timing of nitrate-free intervals in a given patient should be determined according to the patients' typical anginal pattern. During the nitratefree period, suggesting that the patient be covered with another antianginal drug (for example, a beta-blocker or calcium-entry blocker) is prudent to prevent the . ~the ~ potential for a rebound in myocardial ischemia from nitrate w i t h d r a ~ a lIn hospitalized patient receiving continuous intravenous TNG for an acute ischemic syndrome, nitrate-free intervals are not considered. In these patients, if nitrate tolerance develops, the dose of TNG is increased and other antianginal agents are used.

Nitrate Preparations

Table 1shows the various nitrate preparations, their dosages, onset of action, and duration of action. Short-Acting Nitrates

Sublingual nitroglycerin is the treatment of choice for the relief of angina attacks. It is absorbed rapidly and hemodynamic effects can be obtained within 2 minutes after drug administration. Because nitroglycerin tablets are light sensitive, they should be stored in dark containers. Sublingual nitroglycerin tablets should be renewed every 4 to 6 months to ensure complete bioavailability. Oral nitroglycerin spray can dispense metered aerosolized doses of 0.4 mgm of nitroglycerin. This preparation of nitrate may be especially helpful in the elderly for the following reasons: (1) in the presence of dry mucous membranes, the aerosolized dose of nitroglycerin may be more rapidly and completely absorbed than the sublingual tablets of nitroglycerin; and (2) nitroglycerin spray only requires one arm for administration and the fine motor skills and visual activity

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Table 1. DOSE AND PHARMACOKINETICS OF COMMONLY USED NITRATE

PREPARATIONS FOR TREATMENT OF ANGINA PECTORIS

Medication

Sublingual nitroglycerin Aerosol nitroglycerin Sublingual and chewable isosorbide dinitrate

Brand

Nitrostat Tablet Nitrolingual Spray lsordil Sublingual Tablet, Sorbitrate Chewable Tablet

Long-Acting Nitrate Drugs lsordil Tablets Oral isosorbide dinitrate Dilatrate SR Oral isosorbide dinitrate (SR) Oral nitroglycerin (SR) Nitroglycerin Extended Release Capsules Cardilate Oral Oral erythrityl tetranitrate Imdur, lsmo Tablets, Oral isosorbide Monoket mononitrate Nitro-Dur, Nitro-Bid, Transdermal Deponit NTG, Nitrodisc nitroglycerin

Usual Dose (mg)

Onset of Action (min)

Duration of Action

10-30 min 10-30 min 1-2 h

3-6 h 6-10 h 2-8 h Variable 6-8 h 8-14 h

-

SR

=

sustained release; NTG = nitroglycerin

that are required for the handling and administration of the small sublingual nitrate tablets are obviated. The potency of a metered dose of nitroglycerin spray might be slightly less than an equivalent dose of a nitroglycerin tablet. Accordingly, two puffs of aerosol may be necessary to relieve or prevent an angina attack. Chewable and sublingual isosorbide dinitrates have an onset of action slightly slower than sublingual nitroglycerin but have a longer duration of action. Long-Acting Nitrates

Isosorbide Dinitrate. Notwithstanding its low bioavailability because of firstpass hepatic metabolism, isosorbide dinitrate has been for years the oral nitrate of choice for the prevention of angina attacks. Generally, one should start with doses of 10 mg by mouth 2 to 3 times per day, increasing to 20 to 40 mg 2 to 3 times per day. In general, a larger dose is required to overcome hepatic metabolism and obtain a longer duration of action. A typical 3 times a day dosing schedule involves giving isosorbide dinitrate at 8:00 AM, 1:00 PM, and 6:00 PM.This allows for a 5- to 6-hour duration of action of the nitrate and a 12-hournitrate-free interval. Tscsc~llicle-5-Vnnc~1tr~te. recent!^ icnc9rhicl.e-5-rnnnnnitrate. the active metabolite of isosorbide dinitrate, has beenieleased for use in the treatment of angina pectoris. The major advantage of isosorbide-5-mononitrateis that it is completely bioavailable by virtue of the fact that it does not undergo first-pass hepatic metabolism. Transdermal Nitroglycerin. Topical nitroglycerin ointment (2%) applied to the skin (usually the chest or arms) can be efficacious as a long-acting nitrate. It may be especially useful in the elderly by allowing avoidance of more pills in a group of patients already taking numerous oral medications. In addition, it may

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be more effective for nitrate delivery in patients with malabsorption caused by bowel edema from congestive heart failure. Nitroglycerin patches obviate the inherent messiness of the ointment preparation, and as long as the concept of a 12- to 14-hour nitrate-free interval is adhered to, they provide excellent 6- to 14-hour antianginal coverage. The patches may be applied on the chest or arm in the morning and removed at night or vice versa. Beta-Blockers

Beta-adrenergic blocking drugs have been used since the 1970s for treatment of chronic stable angina pectoris. The primary mechanism of action of this class of drugs is the competitive inhibition of the beta-adrenergic receptor. This action results in a decrease in heart rate, reduction in blood pressure (especially systolic blood pressure), and a decrease in myocardial contractility. The effect of betablockers on these hernodynamic parameters is most evident in the setting of stress, such as exercise, wherein release of catecholamines from the sympathetic nervous system and the adrenal medulla is increased. The salutary effect of the betablockers is to decrease myocardial oxygen demand. Clinically, this translates into allowing the patient to perform at a higher level of activity that would have previously provoked angina. Beta-blockers may also improve myocardial oxygen supply by their effects of slowing the heart rate and extending the duration of diastole, the time interval wherein the majority of coronary flow occurs. Table 2 lists the beta-blockers commonly used in the treatment of the angina patient. Beta-adrenergic blockers are classified by cardioselectivity,duration of action, membrane-stabilizing activities, intrinsic sympathetic activity, and lipophilic properties. Two major types of beta receptors exist, beta, and beta,. Beta, receptors occur predominantly in the heart, kidney, and fat cells, whereas beta, receptors occur in the lungs, blood vessels, and liver. Beta-blockers are classified according to whether they are relatively cardioselective (a beta, receptor blocker-metoprolol) or noncardioselective (beta, and beta, receptor blockers-propranolol). A major advantage of cardioselective beta-blockers is that they are less prone to induce bronchospasm as compared to noncardioselective beta-blockers. When one uses higher doses of cardioselective beta-blockers, the drug reacts like a nonselective beta-blocker with the full potential for bronchospasm. Additionally, by blocking beta, receptors, which promote vasodilation, noncardioselective beta-blockers can provoke paradoxical hypertension as well as coronary vasospasm when a catecholamine such as epinephrine (which acts on both alpha and beta receptors) is released during mental stress. In the setting of nonselective beta-blockade the result could be unopposed alpha vasoconstriction (no compensatory beta, vasodilati~n).~~ The various beta-blockers differ in the property of lipid solubility. Lipophilic beta-blockers such as propranolol and metoprolol are rapidly absorbed from the gastrointestinal tract and are predominantly metabolized by the liver. The lipophilic beta-blockers tend to have a short elimination half-life that necessitates they be given 2 to 4 times a day to ensure sustained 24-hour efficacy. In addition, the lipophilic property of these beta-blockers facilitates the transfer of the betablocker across the blood-brain barrier, which potentially increases the risk of central nervous system side effects such as mood changes and sleep disturbances. In contrast to the lipophilic beta-blocker, the hydrophilic beta-blockers such as atenolol and nadolol are not readily absorbed from the gastrointestinal tract

Table 2. PHARMACOI..OGY OF COMMONLY USED BETA-BLOCKERS IN TREATMENT OF ANGINA PECTORIS

Generic Drug (Bra~rid)

Cardioselectivity (Relative B, Sensitivity)

Elimination Half-Life (h)

Intrinsic Sympathetic Activity

Lipophilic Properties

Membrane Stabilizing Activity

Usual Maintenance Dose -

Propranolol (Inderal) Propranolol LA (Inderal-LA) Atenolol (Tenormin) Metoprolol (Lopressor:] Metoprolol ER (Troprol XL) Timolol (Blocadren) Acebutolol (Sectral) Pindolol (Visken) Labetalol (Normodyne) LA = long acting; ER = extended release

high high low moderate moderate low low moderate low

10-40, qid 40-240, qd 25-1 00, qd 25-1 00, bid 50-200, qd 10-20, bid 200-600, bid 5-20, tid 100-600. bid

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and are primarily excreted by the kidney. The hydrophilic beta-blockers have a relatively long elimination half-life, which allows once a day dosing of the drug. Finally, hydrophilic beta-blockers are theoretically less likely to induce adverse central nervous system effects when compared to the lipophilic beta-blockers. Beta-blockers as a class of drugs have effects on serum Iipids. In general, beta-blockers effect no significant changes on total cholesterol or LDL cholesterol, Aronow et but they may increase triglycerides and decrease HDL chole~terol.~~ a16 found that long-term use of propranolol (up to 44 months) did not cause a significant effect on serum total cholesterol, LDL cholesterol, HDL cholesterol, total cholesterol/HDL cholesterol ratio, or triglycerides. Novel beta-blockers such as labetalol, carvedilol, and bucindolol have vasodilator properties in addition to their beta-blocker properties. This feature makes them useful in the management of hypertension and possibly congestive heart failure. Some beta-blockers such as pindolol possess the property of intrinsic sympathomimetic activity (ISA). This property conveys to these beta-blockers a weak beta-agonist activity that usually prevents slowing of the heart rate, depression of atrioventricular conduction, and myocardial contractility in the setting of low sympathetic tone, such as when the patient is resting or sleeping. In the setting of heightened sympathetic tone, the beta-blockers with ISA activity behave as usual beta-blockers with attenuation of heart rate, blood pressure, and contractility. Notably, beta-blockers with ISA activity do not reduce the incidence of sudden death after acute myocardial infarction, a usual feature of other beta-blockers. Ironically, the ISA property itself may militate against a prevention of sudden death by not allowing the beta-blocker to reduce heart rate at rest. Accordingly, beta-blockers with ISA activity are not recommended for patients having had acute myocardial infarction or for patients in whom a decrease in heart rate at rest and during sleep is desirable. Beta-blockers have antiarrhythmic properties and are classified as a TypeImporI1 antiarrhythmic according to the Vaughn Williams' classifi~ation.~~ tantly, beta-blockers are the only antiarrhythmic drug shown to prevent sudden death.4,9Aronow et a15demonstrated that the reduction in sudden death in elderly patients with heart disease and complex ventricular arrhythmias caused by propranolol is due more to an anti-ischemic effect than to an antiarrhythmic effect. Propranolol and metoprolol exhibit debrisoquine-type genetic polymorphism. Slow hydroxylators who have a significantly long elimination half-life may only require once a day dosing of metoprolol, whereas rapid hydroxylators may require 3 times a day dosing.48Furthermore, recent studies have shown that patients of Chinese descent show increased sensitivity to beta-blockers and that the dose of beta-blockers prescribed should be lower in this group of patients.72 In general, beta-blockers are well tolerated; however, undesirable side effects do occur. Common adverse reactions to beta-blockers are listed. Elderly patients may have occult sinus node or AV node disease unmasked by beta-blocker therapy. Beta-blockers are contraindicated in the clinical setting of bronchospasm, hypotension (less than 90 mmHg systolic blood pressure), severe sinus bradycardia, 2" or 3" AV block (unless a pacemaker is in place), severe congestive heart failure, or hypoglycemia-prone diabetes mellitus. Furthermore, sudden abrupt withdrawal of beta-blockers from patients receiving long-term therapy may lead to the provocation of an acute ischemic syndrome such as unstable angina or The mechanism for the beta-blocker withdrawal rebound myocardial infarcti~n.~' phenomenon is unknown but may be related to increased myocardial sensitivity to catecholamines on withdrawal of the beta-blocker. Accordingly, if beta-blockers should be discontinued the dose should be tapered and the patient should be

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Adverse Reactions to Beta-Blockers 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

Fatigue Bradycardia and heart block Mental disturbances (mood changes, nightmares) Dyspepsia Diarrhea or constipation Bronchospasm Skin rash Fever Exacerbation of congestive heart failure Cold hands Raynaud's phenomenon Sexual dysfunction

instructed to decrease his or her activity. Ideally, the patient should be treated with another drug, such as a nondihydropyridine calcium-entry blocker, during the withdrawal phase of beta-blocker therapy. Calcium Blockers

The calcium ion plays a singular role in myocardial contraction, control of peripheral and coronary vascular tone, sinus node function and AV conduction. The calcium ion couples neurogenic excitation with mechanical contraction in cardiac, smooth, and skeletal muscle. When the myocardial cell depolarizes, calcium enters the myocardial cell through calcium channels and triggers the release of stored calcium from the endoplasmic reticulum. Intracellular calcium then combines with troponin and tropomyosin, the primary regulatory proteins of actin and myosin contractile molecules. As a result of this combination, active sites on the actin molecule are exposed. Myosin molecules then bind to these ' ~the smooth muscle of blood vessels, calcium active sites and contraction o c c ~ r s .In that enters the cell through the calcium channel combines with calmodulin, a regulatory protein. The calcium-calmodulincomplex then activates myosin kinase, which phosphorylates the light chain of myosin. The phosphorylation of myosin results in the binding of actin with myosin and this leads to contracti~n.'~ Finally, calcium plays a fundamental role in depolarization and conduction in both the sinus and AV nodes of the heart. The calcium entry blockers, by blocking calcium channels, can favorably decrease myocardial oxygen demand by reducing blood pressure and myocardial contractility.In addition, nondihydro., --. ---:A:-..--.~.--... . , .,.,_ ." :, .- - 1 - : .... .. ..,,..-.--1c.1-~ i ; i i.-..\ Lb~ v U l l L l a L i C l l l call l u l ~llrl r,.. . decrease myocardial oxygen consumption by decreasing heart rate by their action on the sinus node. Calcium entry blockers can improve myocardial oxygen supply by relaxing the tone of coronary arteries. This latter property is especially important when coronary vasospasm such as observed in Prinzmental's angina or socalled mixed angina is present and is a cause of the myocardial i~chemia.~ The calcium entry blockers can be divided into four groups: (1)the dihydropyridines, (2) verapamil, (3) diltiazem, and (4) bepridil. Table 3 shows the pharmacokinetics of the calcium entry blockers approved for use. -..L

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LLU~UIIIII

ULLU

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Table 3. PHARMACOLOGY OF COMMONLY USED CALCIUM ENTRY BLOCKERS IN TREATMENT OF ANGINA PECTORIS

Dihydropyridines

Nifedipine is a potent vasodilator with negative inotropic properties. The negative inotropic properties of nifedipine are attenuated by the increased baroreceptor-mediated sympathetic tone that is induced by the intense vasodilation and drop in blood pressure following drug administration. In fact, an increase in resting heart rate can be expected after administration of a short-acting nifedipine. In some patients this augmentation of the sympathetic nervous system, as well as a postulated coronary steal phenomenon resulting from intense coronaryarteriolar vasodilation induced by nifedipine, may even aggravate the patient's existing angina pectoris." As many as 10% of patients taking nifedipine have an increased frequency of angina attacks. Accordingly, if one wishes to use a shortacting form of nifedipine it should be combined with a beta-blocker to block this increased sympathetic activity.43The new sustained-release preparation of nifedipine, which utilizes the gastrointestinal therapeutic system (GITS) of delivery, does not generally have the property of increased reflex sympathetic stimulation. The delivery system is designed to maintain a constant therapeutic blood level of nifedipine over a 24-hour period. In the doses used clinically, nifedipine does not usually depress sinus node function or AV conduction. Accordingly, it can be used by patients in whom sinus node function or AV conduction is marginal. This may be especially important in the elderly patient who may have occult sick sinus syndrome or AV-node conduction disease. Approximately 10% to 30% of patients taking dihydropyridines develop dependent edema during therapy. This edema is probably not secondary to congestive heart failure and usually responds to low doses of diuretics. The second generation dihydropyridines such as amlodipine and felodipine have a longer plasma half-life, greater vascular selectivity, and less negative inotropy compared to nifedipine. These features allow calciuim-channel blockers to be given once a day and to be given to patients with left ventricular dysfunction. However, these new dihydropyridines should be used cautiously (very low doses)

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or not at all in the elderly because of the potential for high plasma drug levels in this group of patients. Verapamil, as a calcium entry blocker, dilates both systemic and coronary arteries and has a negative inotropic effect on the myocardium. Compared to nifedipine, however, verapamil produces less reflex sympathetic stimulation as a response to a drop in blood pressure. Hence, we do not see the increase in heart rate after verapamil administration and in fact we usually observe heart rate slowing as a result of the drug's action on sinus node automaticity. Verapamil's pharmacologic action of depression of sinus node automaticity and atrioventricular conduction and depression of gastrointestinal motility makes its use in the elderly problematic given their high incidence of sinus and AV-node disease and constipation. Finally, recent data suggest that patients given verapamil after acute myocardial infarction and treated for 1 year have a better prognosis compared to patients given placebo.64The mechanism for this improved prognosis is unknown, but it may be the result of the anti-ischemic property of the drug. Diltiazem is an efficacious calcium-channel blocker with activity similar to but not as potent as verapamil on the sinus node, AV node, and myocardial contractility. In the doses recommended for the prevention of angina pectoris, diltiazem is generally well-tolerated and causes fewer side effects when compared to other calcium entry blockers. However, one must always be alert to the possibility of drug-induced bradycardia and hypotension in the elderly patient receiving diltiazem. Moreover, recent data suggest that chronic diltiazem therapy after myocardial infarction may be deleterious in patients who had heart failure during the acute setting.'j5Findings from the Multicenter Diltiazem Post Infarction Trial (MDPT) show that patients experiencing congestive heart failure during acute myocardial infarction who were randomly assigned to receive diltiazem for 1 year had a higher mortality at follow-up compared to patients with congestive heart failure during acute myocardial infarction who received placebo. Accordingly, we do not recommend that patients who had congestive heart failure during acute myocardial infarction be treated with diltiazem unless the patient's angina cannot be adequately controlled by other antianginal agents. Finally, extended-release diltiazem compounds that allow once a day dosing of diltiazem for angina prophylaxis are now available. Bepridil is a novel calcium entry blocker. In addition to its vasodilatory action and modest depressive activity on the sinus node and AV node, bepridil is a sodium-channel blocker that results in prolongation of atrial and ventricular effective refractory periods. The latter feature gives the drug antiarrhythmic potential. Unfortunately, the drug can also prolong the QTc interval on electrocardiography and cause torsades de pointes. Sudden deaths have occurred in patients taking ~,'j~ if bepridil that have been attributed to this latter m e c h a n i ~ m . ~Accordingly, bepridil is used as an antianginal agent frequent electrocardiograms should be obtained, and if evidence exists of QTc prolongation, the drug should be discontinued. DRUG TREATMENT OF STABLE ANGINA

For patients who have infrequent angina attacks (less than two angina attacks per week), sublingual nitroglycerin, which can be used either as angina prophylaxis or for the treatment of a spontaneous angina attack, may be the only drug necessary for medical management. However, for patients with more frequent angina (two or more attacks per week), a long-acting antianginal drug such as

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either a long-acting nitrate, a beta-blocker, or a calcium entry blocker should be prescribed. Studies show that head-to-head comparisons of representative members of these three classes of antianginal drugs generally show equal efficacy in regard to angina prophylaxis and improvement in exercise. Thus, the choice of which antianginal drug to prescribe should be made on clinical grounds. For example, a long-acting nitrate or calcium entry blocker, but not a beta-blocker, should be used in a patient with angina and asthma, whereas a beta-blocker may be the drug of choice in a patient with angina who had a recent myocardial infarction-as long as the patient does not have any contraindications for betablockade. Combination therapy using two drugs should be considered if angina persists and is intolerable despite titration of monotherapy to maximally tolerated doses. The addition of a beta-blocker to a long-acting nitrate is theoretically a synergistic combination for the prevention of angina. A nitrate decreases myocardial oxygen consumption by decreasing wall tension, but it may increase heart rate and it has no effect on myocardial contractility. Beta-blockers decrease heart rate and contractility, but increase intracardiac volume. Nitrates block this potential increase in heart volume. In addition, nitrates increase myocardial oxygen supply by relaxing coronary vasculature and reducing left ventricular end-diastolic pressure. Beta-blockers have the potential for inducing coronary vasospasm by their promotion of the vasoconstricting action of unopposed alpha sympathetic stimulation of the coronary vasculature. Clinical studies have shown that combination therapy with a nitrate and a beta-blocker decreases the number of angina attacks and increases the duration of time on treadmill stress testing as compared to either nitrates or beta-blockers a10ne.~ Combination of a beta-blocker with a calcium blocker also reduces angina However, be careful in and extends treadmill time compared to m~notherapy.~' combining a beta-blocker with either diltiazem or verapamil. This combination has the potential for severe bradycardia (sinus bradycardia, junctional rhythm, or heart block). Thus, this combination should not be used in patients with sinus node dysfunction or AV nodal disease. Additionally, when used, start with the lowest dose of each of the drugs and monitor the patient carefully. Because a beta-blocker and both diltiazem and verapamil have negative inotropic properties, their combination could precipitate congestive heart failure in a patient with borderline left ventricular function.55Accordingly, the combination of beta-blocker plus either diltiazem or verapamil is best avoided in those patients with left ventricular dysfunction. If one wants to use a beta-blocker with a calcium entry blocker in a patient with left ventricular dysfunction, choosing a dihydropyridine derivative (either nifedipine, amlodipine, or felodipine) as the calcium entry blocker may be safer. Nevertheless, the patient with left ventricular dysfunction should be monitored carefully for any signs of congestive heart failure. The combination of a calcium entry blocker with a long-acting nitrate may be efficacious in reducing angina and improving exercise tolerance, but risk of hypotension exists because both drugs are vasodilators. This is especially important in the elderly patient prone to hypotension. To avoid significant hypotension, low doses of both drugs should be used. Additionally, hypotension can be prevented if the drugs are not administered together, but are administered 1 or 2 hours apart. This prevents simultaneous onset of action of the drugs. In the angina patient who cannot tolerate a beta-blocker because of side effects or contraindications, the combination of a long-acting nitrate and diltiazem, which has similar synergism to the long-acting nitrate and beta-blocker combination by virtue of diltiazem's effect on heart rate and myocardial contractility, is an excellent antianginal regimen.

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When angina persists despite optimal dosing of a double drug combination of antianginal drugs then a triple drug combination should be tried. This triple drug combination includes a long-acting nitrate, a beta-blocker, and a calcium entry blocker. Though randomized, double-blind controlled studies have not conclusively shown that triple combination therapy is better at reducing angina, reducing sublingual nitroglycerin usage, or improving exercise treadmill times than is double drug combination therapy in patients with chronic stable angina, clinical experience suggests that triple drug combination can be beneficial in improving symptoms i n selected patients with severe angina. UNSTABLE ANGINA

Unstable angina is now the most frequent diagnosis of patients discharged from coronary care units for chest pain. Traditionally, unstable angina has been considered an intermediate syndrome between chronic stable angina and myocardial infarction. The diagnosis of unstable angina includes patients with new-onset angina and patients with chronic angina who have a change in their angina pattern as demonstrated by an increase in frequency, duration, and severity of angina attacks, especially when the attack occurs at rest. Electrocardiographic changes of left ventricular ischemia such as ST-segment depression can usually be demonstrated in these patients during spontaneous angina attacks. Recently BraunwaldI3 has developed a new classification of the various subgroups of patients with unstable angina. This classification is helpful in evaluating various treatment outcomes as well as in defining high-risk patients with unstable angina. Recent studies using contrast angiography, coronary ultrasound, coronary angioscopy, and pathologic specimens have provided insight into the pathogenesis The initiating event of unstable angina may be the fissuring of unstable angina.2*23,61 of a vulnerable atherosclerotic plaque in the coronary artery.23The cause of plaque fissure formation is unknown. Some workers have suggested that the plaque fissure is the result of hemodynamic factors within the coronary lumen, such as shear stress. These workers point out that the plaque fissure occurs usually at the weakest point of the fibrous plaque, known as the shoulder regionz2Other researchers suggest that the plaque fissures as a result of the proteolytic action of metalloproteinases released by macrophages within the atherosclerotic plaque. These researchers provide data showing that activated macrophages exist at the site of a recent plaque fissure.33By whatever mechanism the formation of a plaque fissure results in various degrees of intraplaque hemorrhage with thrombus overlying the fissure. Intraplaque hemorrhage results in a change in the geometry of the atherosclerotic plaque that may lead to a further narrowing of an already narrowed coronary artery. The initial intracoronary artery thrombus is usually a platelet-rich (white) thrombus and is later transformed to a more fibrin-rich (red) thrombus. The disruption of the intima by the fissure may also result in local ? ? ? ~ t > h, ! pr c m n z r v rl>cr\m.'tic? - - - - -! p -z -r.l i-ng- t, - -c ~ :rzScSn.?qI T..-..-. S+rr?tnn;n ~ ~. zn.4 -.-. -. thromboxane A2released from platelets may contribute to the coronary vasospasm, especially in the downstream micro~irculation.~~ Autopsies have shown embolic platelet emboli in the microcirculation of patients dying of acute coronary synd r o m e ~The . ~ ~fissured plaque of a patient with unstable angina is dynamic in nature and unstable. The final clinical outcome of a plaque fissure, whether unstable angina or myocardial infarction, will be determined by the size of the fissure, the size of the thrombus, the extent of intraplaque hemorrhage, the size of the preexisting atherosclerosis plaque, and the extent of preexisting collateralcoronary ~

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artery circulation. Total occlusion of a coronary artery in the absence of effective coronary collaterals results in myocardial infarction, whereas subtotal occlusion of the coronary artery may result in unstable angina. Given time the unstable plaque with fissure and thrombus heals. The thrombus either dissolves by intrinsic mechanisms or becomes organized by the fibrous tissue. If the thrombus undergoes organization by fibrous tissue, then the initial atheroscleroticplaque may increase in size.33Four to 6 weeks are required for the unstable coronary plaque to fully endothelialize. The key to medical management of the patient with unstable angina is to rapidly stabilize the unstable atherosclerotic plaque, which should translate into improved clinical outcome. Patients with unstable angina should be admitted to a coronary care unit. Extracardiac factors such as severe anemia and hyperthyroidism should be looked for and treated accordingly. Medical management includes electrocardiographic monitoring, oxygen administration, antiplatelet therapy, intravenous nitrates, antithrombotic therapy, beta-blockers, and calcium-channel blockers. Patients should be monitored for at least 24 hours, longer if the patient has continuous anginal attacks despite medical management. Continuous nasal oxygen should be given at 1to 2 L/min if the patient is having pain, any evidence of heart failure exists, or if any other conditions are present that may cause hypoxemia. Oxygen therapy can be guided by blood gases or by noninvasive pulse oximetry determinations. The patient should be given aspirin (325 mgm) orally on admission and every day thereafter. Substantial evidence shows that aspirin therapy for unstable angina reduces death and infarction compared to p l a c e b ~ . ' ~To , ~facilitate ~ , ~ ~ the rapid antiplatelet effect of aspirin, we generally have the patient chew the first dose of aspirin. Thereafter, to prevent gastrointestinal distress, we use the enteric coated fbrmulation of aspirin. For patients with unstable angina and episodes of rest pain, we generally treat with continuous intravenous nitroglycerin for at least 24 hours. We start at a dose of 10 pg/min and increase the dose by 10 pg every 2 minutes until chest pain is relieved or a decrease in systolic blood pressure of 10 mmHg or an increase in heart rate of 10 beats per minute or both occur. The usual dose of intravenous nitroglycerin used in the treatment of unstable angina varies from 10 to 100 pg/ min. When the patient is angina free for 24 hours he or she can be switched to an oral or transdermal preparation of nitrates. For patients with less severe unstable angina and without ongoing rest pain or electrocardiographic evidence of ischemia, transdermal nitroglycerin may be considered instead of intravenous nitroglycerin therapy. For patients with unstable angina, restpain, and e&ctrocardiographic changes who do not have any contraindications for anticoagulation, continuous intravenous heparin should be started and maintained for at least 48 hours. Patients should initially be given a 5000 unit intravenous bolus followed by an intravenous infusion of 100 U/h. Activated partial thromboplastin times (aPTT) should be maintained at 2 to 3 times control, which is usually about 60 seconds. Activated PTT levels should ideally be obtained every 6 hours. In considering heparin therapy, the risks of bleeding must be weighed against the possible benefits. Recent studies suggest that older patients, patients with systolic blood pressure elevation greater than 180 mmHg, women, and patients with reduced weight have an increased risk of bleeding when treated with heparin.39Moreover, the additional clinical benefits of combining heparin therapy with antiplatelet therapy for patients with unstable angina are only moderate.67Nevertheless, we still recommend heparin therapy in the high-risk patient with unstable angina as long as the patient is carefully selected.

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Some patients with unstable angina treated with heparin may have a heparin withdrawal-rebound phenomenon when heparin is discontinued. Small studies show that some of these patients several hours after the discontinuation of heparin have an abrupt increase of their angina.@Accordingly, the clinical phenomenon should be looked at after heparin is discontinued and heparin therapy should be immediately restarted if the patient has any exacerbation of symptoms. Beta-blockers should be considered in patients with a relative increase in heart rate (heart rate > 70 beats per minute) and a systolic blood pressure greater than 100 mmHg. However, one should look carefully for contraindications of beta-blockers before giving them to the elderly patient with unstable angina. Calcium-channelblockers should be considered for patients with ongoing angina despite aspirin, heparin, nitrate, and beta-blocker therapy. Nifedipine should not be used without a beta-blocker in the patient with unstable angina. Studies show that treatment of the patient with unstable angina with nifedipine alone leads to a worse prognosis.37 Fortunately, more than approximately 90% of patients with unstable angina can be stabilized with medical management." However, coronary angiography should strongly be considered in those patients in whom one suspects left main coronary disease or three vessel coronary disease plus left ventricular dysfunction, because in both of these conditions prognosis is improved by coronary artery bypass surgery. Patients with a history of previous percutaneous transluminal coronary angioplasty (PTCA) should have early angiography because the syndrome of unstable angina may be the result of re-stenosis of the prior PTCA lesion. Patients having had prior bypass surgery should also be considered for early angiography. lnvother hatients; decision f i r coronary angiography during initial hosvitalization should be individualized with the help of noninvasive testing. For example, low-level exercise stress testing can usually be performed safely on patients with unstable angina who are pain free for at least 3 days. ButmanI7 showed that patients with unstable angina who were medically stable and had positive exercise stress tests had more clinical events at follow-up (death, myocardial infarction, unstable angina, or need for revascularization)compared to patients with negative stress tests. Other noninvasive tests such as 24-hour ambulatory Holter monitoring, dipyridamole thallium scintigraphy,or dobutamine echocardiography can be considered in patients who cannot exercise. Patients with myocardial ischemia detected by any of these tests should be considered for early angiography because studies show that they are at increased risk of cardiac events at follow-up. Reassuringly, data from the recent thrombolysis in myocardial infarction (TIMI)l l l B study, which compared early invasive therapy with conservative therapy in patients with unstable angina, showed that patients assigned conservativetherapy (which dictated that the patient undergo angiography and revascularization only for clinical reasons such as spontaneous or inducible angina) had a similar outcome when compared to those patients assigned to early invasive therapy.'j6 The remaining 10% of patients whose disease is refractory to medical management are at high risk of cardiac events, myocardial infarction, and death.54Accord;s-..-.!~~ "'b'y,

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a revascularization procedure (either PTCA or coronary artery bypass surgery). These patients may need stabilization by intra-aortic balloon pumping before coronary angiography. In the future, more aggressive antithrombotictherapy and antiplatelet therapy may be available for management of the patient with unstable angina. Hirudin, which is derived from the leech Hirudo medicinals, is a direct thrombin antagonist and is the most potent naturally occurring anticoagulant. Current recombinant formulations of hirudin are undergoing extensive clinical trials. Available data

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suggest that improvement occurs in coronary artery thrombus dissolution or prevention of t h r o m b u s accumulation with hirudin as compared with heparin.59 Whether this translates into a n improved clinical outcome for the patient with unstable angina will b e determined by large clinical trials such as t h e ongoing Global Use of Strategies t o O p e n Occluded Arteries (GUSTO)-2 Trial. Blockade of t h e platelet II8/IIIA receptor by newer drugs or monoclonal antibodies produces severe platelet dysfunction greater than that produced by aspirin alone. Small controlled clinical studies of patients with unstable angina have s h o w n that this treatment strategy improves clinical outcome compared to placebo especially i n those patients requiring PTCA for refractory angina.62Further studies a r e needed to determine whether this form of therapy will improve the prognosis of the patient w i t h unstable angina.

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42. Jajich CL, Ostfeld AM, Freeman DH: Smoking and coronary heart disease mortality in the elderly. JAMA 252:2831-2834, 1984 43. Johnston DL, Lesoway R, Humen DP, et al: Clinical and hemodynamic evaluation of propranolol in combination with verapamil, nifedipine and diltiazem and exertional angina pectoris: A placebo-controlled, double blind, randomized crossover study. Am J Cardiol 55:680-687, 1985 44. Kern MJ, Ganz P, Horowitz JD, et al: Potentiation of coronary vasoconstriction by beta adrenergic blockade in patients with coronary artery disease. Circulation 67:11781185, 1983 45. Kukovetz WR, Holzmann S: Mechanisms of nitrate-induced vasodilation and tolerance on a biochemical base. Z Kardiol 74(suppl. 1):39-44, 1985 46. Lavie CJ, Milani RV, Littman AB: Benefits of cardiac rehabilitation and exercise training in secondary coronary prevention in the elderly. J Am Coll Cardiol22:678-683,1993 47. Lehtonen A: Effect of beta-blockers on blood lipid profile. Am Heart J 109:1192-1196,1985 48. Lennard MS: The polymorphic oxidation of beta-adrenoceptor antagonists. Pharmacol Ther 41:461, 1989 49. Lewis HD, David JW, Archibald DG, et al: Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Engl J Med 309:396403, 1983 50. Miller RR, Olson HG, Amsterdam EA, et al: Propranolol withdrawal rebound phenomenon: Exacerbation of coronary events after abrupt cessation of antianginal therapy. N Engl J Med 293:416-418,1975 51. National Center for Health Statistics: Advance Report of Final Mortality Statistics, 1988 Monthly Vital Statistics Report. Hyattsville, Maryland, Public Health Service 39(suppl. 7):7-1-48, 1990 52. National Hospital Discharge Survey. Washington, DC, United States Department of Health and Human Services, National Center for Health Statistics, 1987 53. Olesen J: Hemodynamics. In Olesen J, Tfelt-Hansen P, Welch KMA (eds): The Headaches. New York, Raven Press, 1993, p p 209-222 54. Olson HG, Lyons KP, Aronow WS, et al: The high risk angina patient: Identification by clinical features, hospital course, electrocardiography and technetium-99m stannous pyrophosphate scintigraphy. Circulation 64:674-684, 1981 55. Packer M: Combined beta adrenergic and calcium-entry blockade in angina pectoris. N Engl J Med 320:709-718, 1989 56. Parker JO: Nitrate therapy in stable angina pectoris. N Engl J Med 316:1635-1642,1987 57. Parker JO, Farrell B, Lahey KA, et al: Effect of intervals between doses on the development of tolerance to isosorbide dinitrate. N Engl J Med 316:1440-1444, 1987 58. Przybojewski JZ, Heyns MH: Acute coronary vasospasm secondary to industrial nitroglycerin withdrawal. S Afr Med J 63:158-162,1983 59. Serruys PW, Deckers JW, Close P: A double blind, randomized heparin controlled trial evaluating acute and long term efficacy of r-Hirudin in patients undergoing angioplasty. Circulation 90:I-394, 1994 60. Shapiro W, DiBianco R, Thadani U, and the Bepridil Collaborative Study Group: Comparative efficacy of 200, 300 and 400 mg of bepridil for chronic stable angina pectoris. Am J Cardiol55:36C-42C, 1985 61. Sherman CT, Litvack F, Grundfest W, et al: Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 315:913-919, 1986 62. Simoons ML, DeBoer MJ, Van Den Brand JBM, and the European Cooperative Study Group: Randomized trial of GP IIb/IIIa platelet receptor blocker and refractory unstable angina. Circulation 89:596-603, 1994 63. Singh B, Courtney KP: The classification of antiarrhythmic mechanisms of drug action: Experimental and clinical considerations. In Zipes DP, Jalife J (eds): Cardiac Electrophysiology: From Cell to Bedside. Philadelphia, WB Saunders, 1990, p 882 64. The Danish Study on Verapamil in Myocardial Infarction: The effect of verapamil on mortality and major events after myocardial infarction: The Danish Verapamil Infarction Trial I1 (DAVIT 11). Am J Cardiol 66:779-785, 1990 65. The Multicenter Diltiazem Post Infarction Trial Research Group: The effect of diltiazem on mortality and reinfarction after myocardial infarction. N Engl J Med 319:385-392,1988

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66. The TIM1 I11 B Investigators: Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Circulation 89:1545-1556, 1994 67. Theroux P, Ouimet H, McCans J, et al: Aspirin, heparin or both to treat unstable angina. N Engl J Med 319:1105-1111,1988 68. Theroux P, Waters D, Lam J, et al: Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 327:141-145,1992 69. Wei JY: Heart disease in the elderly. Cardiovascular Medicine 9:971-982,1984 70. Wei JY: Cardiovascular anatomic and physiologic changes with age. Topics in Geriatric Rehabilitation 210-16, 1986 71. Wenger WN, Marcus FI, O'Rourke R: Cardiovascular disease in the elderly. J Am Coll Cardiol 10:80A-87A, 1987 72. Wood AJ, Ahou HH: Ethnic differences in drug disposition and responsiveness. Clin Pharmacokinet 20:350-373, 1991

Address reprint requests to Harold G. Olson, MD Cardiology Section Veterans Administration Medical Center 5901 East Seventh Street Long Beach, CA 90822