911

Medical Treatment of Stable Angina

James J. Ferguson III, Dipsu D. Patel, and James T. Willerson

Key Points

• Therapy is directed at reducing heart rate, blood pressure, and contractile responses to exercise and stress, so that myocardial oxygen demand for any given activity is reduced. Medication and interventions that increase coro-nary blood flow and oxygen delivery may also be useful.

• The heart rate–systolic blood pressure product provides an estimate of myocardial oxygen demand.

• Stable angina can usually be relieved promptly by rest and nitroglycerin.

• Exogenously administered nitrates increase oxygen deliv-ery to the subendocardial region supplied by a severely narrowed coronary artery.

• One should not use nitrates and erectile dysfunction medications (sildenafil, vardenafil, or tadalafil) within 24 hours of one another as the combination may cause pro-found hypotension.

• β-adrenergic antagonists attenuate heart rate, systolic blood pressure, and contractile responses at rest and during exercise.

• Selected beta-blockers reduce mortality and repeated hos-pitalization risks in patients with prior myocardial infarctions, heart failure, and hypertension.

• Beta-blockers may cause bradycardia, bronchospasm, hypotension, atrioventricular (AV) block, and depression of myocardial contractility. They may also exacerbate coro-nary artery spasm and make it more frequent and severe.

• Slow calcium channel antagonists relax vascular smooth muscle and increase coronary blood flow. They are divided into two major classes: dihydropyridines (nifedipine and amlodipine) and the nondihydropyridines (diltiazem and verapamil). The nondihydropyridine calcium antagonists decrease AV conduction and sinus node impulse forma-tion while increasing coronary blood flow. The dihy-dropyridine calcium antagonists do not decrease AV

conduction and sinus impulse formation but do increase coronary blood flow.

• The nondihydropyridines have significant negative ino-tropic effects and should not be given to patients with clinically significant congestive heart failure (CHF).

• Angiotensin-converting enzyme (ACE) inhibitors may improve endothelial function in patients with stable coronary heart disease.

• The risk of myocardial infarction in patients with coro-nary heart disease is reduced with aspirin.

• Meta-analysis in various clinical studies have suggested 75 to 150 mg of aspirin daily in patients at high risk for myocardial infarction.

• Clopidogrel in combination with aspirin may be bene-ficial in those patients with established coronary disease.

• To date, oral IIb/IIIa platelet antagonists have not been protective, and some studies show possible harm.

• Chronic oral anticoagulation therapy after myocardial infarction reduces the combined end points of mortality and nonfatal reinfarction while increasing bleeding risks.

• Patients with known or suspected coronary heart disease should avoid smoking, rigorously control their serum cholesterol with the lowest low-density lipoprotein (LDL) possible, reduce their triglycerides, control their blood pressure and hyperglycemia, and get regular exercise.

• Evidence suggests that estrogen and progestin do not prevent clinically significant coronary heart disease.

• The cyclooxygenase (COX-2) inhibitors that increase blood pressure appear to slightly increase the risk of future vascular events (i.e., valdecoxib). Other COX-2 inhibitors used in low dose, such as celecoxib probably do not sig-nificantly increase the risk of future vascular events.

Patients with stable angina usually have angina with effort, exercise, or emotion; after eating relatively large meals;

38

Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 913β-Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . 913Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 915Angiotensin-Converting Enzyme Inhibitors. . . . . . . . . . 917

Platelet Antagonists. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919Risk Factor Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 925Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 929Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 931

912 c h a p t e r 38

or during other stressful circumstances that increase myocardial oxygen demand by increasing heart rate, contrac-tile state, or ventricular wall tension. Cold exposure also causes angina as a result of increasing myocardial wall tension, as a consequence of increased blood pressure, and through coronary artery vasoconstriction.

Therapy is directed at reducing heart rate, blood pressure, and contractile responses to exercise and stress, so that myo-cardial oxygen demand for any given activity is reduced. Medication and interventions that increase coronary blood flow and oxygen delivery may also be useful. In individual patients, stable angina often develops in a predictable manner and at a level of activity or stress associated with a particular systolic blood pressure and heart rate. The heart rate–systolic blood pressure product provides an estimate of myocardial

oxygen demand. Some patients have occasional episodes of angina at rest or with slight physical effort, possibly as a result of transient coronary artery vasoconstriction. In addi-tion, the amount of effort required to cause angina may vary from time to time in individual patients. Some patients have angina as they begin exercise, which disappears as they exer-cise further (“walk-through angina”). Pharmacologic therapy used in the treatment of patients with stable angina is described below. The primary objectives of medical therapy are to reduce myocardial oxygen demand for any level of activity and to increase myocardial blood flow to vulnerable regions of the heart. This can be accomplished with a variety of agents, including nitrates, β-adrenergic agonists, calcium channel antagonists, and angiotensin-converting enzyme (ACE) inhibitors.

H3CH2C

H2CH2C

H2C

CH2

O2N

O2N CH2

O

O OH2CO2N O

CH

NO2O

H2C NO2O

NO2O

O

O

C

HC

NO2

NO2CH2 O NO2

NO2O O

H2C NO2O

CHHC

NO2OHC

NO2OHCHC

H3CCHCH2CH2ONO

Amyl nitrate(isoamyl nitrate)

Nitroglycerin(glyceryl trinitrate, nitro-bid

nitrostat, others)

Isosorbide dinitrate(isordil, sorbitrate, others)

Erythrityl tetranitrate(cardilate)

Pentaerythritol tetranitrate(pentritol, peritrate, others)A

Organic nitrates

Nitroprusside

Nitric oxide(NO)

formation

Conversion toS-nitrosothiols

Guanylatecyclase

cGMP

Relaxation

GTP

Vascular smoothmuscle cell

C

FIGURE 38.1. (A) The chemical structures for selected nitrate prepa-rations. (B) Nitroglycerin’s physiologic effects in the heart and in the peripheral venous system. Nitroglycerin dilates large and medium-sized coronary arteries and improves myocardial blood flow to the subendocardial region. In the systemic circulation, nitroglycerin is a venodilator; therefore, it decreases venous return to the right heart and diminishes preload and wall tension, thereby decreasing myo-cardial oxygen demand. (C) The cellular biochemical effects of nitrates that correlate with their properties as coronary artery vaso-dilators. The nitrates increase guanylate cyclase activity, resulting in an increase in cyclic guanosine monophosphate (cGMP), which is associated with vasodilatation. It is believed that nitroglycerin exerts its endothelium-independent vasodilating effect through the activa-tion of guanylate cyclase and the cellular increases in cGMP. GTP, guanosine triphosphate.

Hea

rtS

yste

mic

circ

ulat

ion

Decrease inVenous returnto the rightheart withconsequentwall tensiondemandreduction

Nitroglycerindilatessystemicveins

Systemicveins

Systemicarteries

Nitroglycerindilates largeand medium-sized coronaryarteries

With consequentincrease incoronary bloodflow tosubendocardialregion

B

m e dic a l t r e at m e n t of s ta b l e a ng i n a 913

dinitrate, are given at 6- to 8-hour intervals and isosorbide mononitrate once or twice during the day.1,4,9 In high-risk patients, a nitroglycerin patch or paste is applied during the nighttime hours and removed the following morning after the patient arises. This approach maximizes the systemic availability of the nitrate and reduces the development of tolerance to the drug.10,11 Patients with stable angina should be cautioned about the absolute contraindication between concomitant use (within 24 hours of either drug) of nitrates, sildenafil, and other similar erectile dysfunction drugs that increase local concentration of cyclic guanosine monophos-phate (cGMP) (i.e., vardenafil and tadalafil). This combina-tion may lead to serious, prolonged and life-threatening hypotension.12

b-Adrenergic Antagonists

β-adrenergic antagonists attenuate heart rate, systolic blood pressure, and contractile responses at rest and during exer-cise (Tables 38.2 to 38.4). Through these effects, selected beta-blockers have been shown in numerous trials to have

TABLE 38.1. Nitrate preparations used in the treatment of angina pectoris

Preparation Dosage Duration of effect Frequency of administration

Sublingual nitroglycerin 0.3–0.5 mg 15–30 min For individual episodesSublingual or chewable isosorbide dinitrate 2.5–10 mg 30 min–1 h May be used instead of nitroglycerinOral isosorbide dinitrate (Isordil) 5–30 mg 2 h Every 2–3 h while patient is awakeOral isosorbide mononitrate (Ismo) 10–20 mg 24 h DailyOral isosorbide mononitrate (Imdur) 30–60 mg 24 h DailyOral isosorbide dinitrate (Tembid), longer- 40 mg 6–8 h Every 6–8 h

acting preparationPentaerythritol tetranitrate (Peritrate)

Oral 10–40 mg 3–4 h Every 3–4 hSustained 80 mg 8–10 h Every 8–10 h

Sustained-release oral nitroglycerin 2.5–6.5 mg 6 h Every 6 h(Nitro-Bid)

Nitroglycerin ointment Thin film on 1– 2 inches 4–6 h Every 4–6 h over small area of anterior chestNitroglycerin patches (sustained release) 0.1 mg/h, 0.2 mg/h, Approximately 12 h Every 12–24 h 0.4 mg/hNitroglycerin spray (Nitrolingual) 1 puff prn Few minutes Prn for chest pain

Nitrates

Stable angina can usually be relieved promptly by rest and nitroglycerin. The beneficial effects of nitroglycerin and other nitrates are the result of venodilatation of systemic veins and a decrease in venous return to the right heart, thereby reducing myocardial wall tension and oxygen demand, and a coronary vasodilator effect involving large and medium-sized coronary arteries, with a consequent increase in coronary blood flow to the subendocardial region where the imbalance between oxygen supply and demand exists (Fig. 38.1).1–9 Nitrates increase oxygen delivery to the suben-docardial region supplied by a severely narrowed coronary artery. Most other coronary vasodilators increase coronary blood flow and oxygen delivery to the epicardium or midmyo-cardium without directly changing oxygen availability within the subendocardial region itself. The coronary vaso-dilator effect of nitroglycerin is associated with an increase in endothelial guanylate cyclase activity and a consequent increase in cyclic guanosine monophosphate. Exogenously administered nitrates can serve as a nitric oxide donor, increasing the availability of nitric oxide in the vasculature and contributing both to the vasodilator response and to reducing platelet aggregation and possibly inflammation, especially at sites of endothelial injury. The nitrate coronary vasodilator effect is endothelium independent (Fig. 38.1).

The physiologic effects of nitrates to increase coronary blood flow and myocardial oxygen availability and decrease myocardial oxygen demand usually relieve angina promptly, that is, within 5 to 7 minutes. The commonly used nitrate preparations are listed in Table 38.1.

The various nitrate preparations differ primarily with regard to the time required for onset of the antianginal effect, the duration of that effect, and the degree to which tolerance develops. The sublingual tablets and oral spray have the fastest onset of any of the preparations and are often used immediately prior to activity. Typically, relatively long-acting and orally administered nitrates, such as isosorbide

TABLE 38.2. Side effects of b-adrenergic antagonists

Easy fatigabilityInsomniaDizziness or syncopeDyspnea with effortSexual impotenceBronchospasmBradycardiaHeart blockHypotensionMore difficult to recognize hypoglycemia in the insulin-

dependent diabetic

914 c h a p t e r 38

TABLE 38.4. Relative contraindications to the administration of b-adrenergic antagonists

Severe congestive heart failure* Severe peripheral vascular diseaseMarked bradycardia (heart rate <55 beats/min) Insulin-dependent diabetes mellitus that is poorly controlled and labileAdvanced atrioventricular block (first-, second-, Sexual impotence or third-degree) BronchospasmSystemic arterial hypotension (systolic blood Coronary artery spasm

pressure <90 mm Hg)

* Selected patients with severe heart failure treated chronically with low and then very gradually increas-ing doses of beta-blockers are symptomatically improved during the course of weeks to months.

TABLE 38.3. Indications for b-adrenergic antagonists in patients with stable angina

Prevent development of angina at relatively low heart rate-systolic blood pressure product

Treat exercise-induced ventricular arrhythmiasTreat systemic arterial hypertension

mortality benefits in patients with hypertension, after myo-cardial infarctions, and heart failure.13,14 Beyond mortality benefits, reductions in heart rate–systolic blood pressure for any particular level of activity may reduce myocardial oxygen demand enough to allow a patient to engage in a particular activity without angina, whereas previously that was not possible. This is primarily accomplished through heart-rate reductions that preferentially prolong diastole, and therefore the time during which coronary perfusion occurs. The beta-blockers most commonly used in the treatment of stable angina are listed in Table 38.5. Beta-blockers are classified as β1- or nonspecific beta-blockers (Fig. 38.2); see also (Table 38.5).15–22 β1-specific blockers, such as metoprolol, alter heart rate and myocardial contractile responses, but at low doses may interfere less with smooth muscle dilatation. At higher doses, the “selective” beta-blockers have physiologic effects more like those of nonspecific beta-blockers and may attenu-ate bronchial and smooth muscle dilatation and exacerbate bronchospasm. Nonspecific beta-blockers, such as proprano-lol, reduce heart rate and myocardial contractile state and interfere with bronchial and vascular smooth muscle dilata-tion. Therefore, the β1-specific blockers given in reduced dosage may have certain advantages in patients with chronic obstructive pulmonary diseases. They may also reduce insulin release less than nonspecific blockers and therefore may be of advantage in the treatment of selected patients with diabetes.

Beta-blockers may cause bradycardia, bronchospasm, hypotension, atrioventricular (AV) block, and depression of myocardial contractility. They may also exacerbate coronary artery spasm and make it more frequent and severe. There-fore, they should not be used in patients with bradycardia, hypotension, AV block, or severe bronchopulmonary lung disease (especially in those with bronchospasm), or coronary artery spasm. They are used with great caution, and initially in very reduced doses, when they are used in patients with clinically severe heart failure. They should also be used with caution in patients with important peripheral vascular disease and insulin-dependent diabetes mellitus, particu-

Agonist hormone

G protein

AdenylatecyclaseGDP

GDPGDP

β-adrenergicreceptor

CyclicAMP

ATP

Kinase(Active)

Kinase(Inactive)

Phosphorylation

Contraction of heart muscle

β

β

β

γ

γ

γ

α

α

α

FIGURE 38.2. The cellular basis for the ability of β-adrenergic antagonists to interfere with agonist stimulation of β-adrenergic receptors. Released from synaptic terminals, catecholamines enhance cardiac output and maintain arterial diffusion pressure. β-adrenergic receptor binds the catecholamines. Catecholamines are released at the synapse, leading to enhanced heart rate and con-tractile force, through the following mechanisms: (1) sympathetic nerve terminals release norepinephrine, which binds to the β-adren-ergic receptor, activating adenylate cyclase through the coupling effect of G proteins; (2) the increase in intracellular cyclic adenosine monophosphate (AMP) leads to activation of protein kinase A; and (3) protein kinase A phosphorylates a variety of proteins, which enhances their catalytic activity, promoting a calcium-dependent increase in cardiac contractility. ATP, adenosine triphosphate; GDP, guanosine diphosphate; GTP, guanosine triphosphate.

m e dic a l t r e at m e n t of s ta b l e a ng i n a 915

larly when the blood glucose has been labile and difficult to control. Increasing in popularity are sustained-release beta-blockers that can be administered once a day and have a sustained release into the systemic circulation, resulting in attenuation of β-adrenergic responses throughout the day (Table 38.5). A beta-blocker should be considered as therapy in the patient who experiences angina at a relatively low level of physical activity or stress. Beta-blockers are often used in conjunction with nitrates to treat exercise- or stress-related angina.

Calcium Antagonists

Slow calcium channel antagonists alter slow calcium channel transport into the cell (Fig. 38.3) and (Tables 38.6 to 38.8).23–46

As a result, these agents relax vascular smooth muscle and increase coronary blood flow. The slow calcium channel antagonists are divided into two major classes: dihydropyri-dines and the nondihydropyridines (comprised of the phenyl-alkylamines and modified benzothiazepines).

The nondihydropyridines are distinguished from the dihydropyridines primarily on their effect on AV node con-duction. Two of these slow calcium channel antagonists,

TABLE 38.5. Selected b-adrenergic antagonists

Beta-blockadepotency ratio Usual therapeutic Elimination

Name (propranolol = 1.0) Cardioselective dose range (mg/day) half-life (h) Route of excretion

Propranolol 1.0 0 80–480 3.5–6.0 Urine(nonspecific)

Timolol 6.0 0 5–40 4–5 UrineOxprenolol 0.5–1.0 0 40–360 2 UrineSotalol 0.3 0 80–480 5–13 UrineMetoprolol (β

1) 1.0 + Given IV at 5 mg in each 3–4 Urine

of 3 doses at 2-min intervals, given orally at 100–800Pindolol 6.0 0 2.5–30.0 3–4 UrineAtenolol (β

1) 1.0 + 100–400 6–9 Approximately 40%

of unchanged drug in urineAlprenolol 0.3 0 200–800 2–3 UrineAcebutolol (β

1) 0.3 + 400–800 8 Uncertain

Nadolol 0.5–1.0 0 40–80 20–24 UrineSotalol* 1 1 80–640 12 UrineEsmolol† (β

1) 0.025 + Given IV at 25– 12 Hydrolysis by

300 mg/kg/min plasmaLabetalol 0.3 Selective alpha- and Given IV 0.25 mg/kg over 8–10 Urine and bile nonselective beta- 2 min and additional blockers 40–80 mg at 1-h intervals, given orally 200–400Toprol Selective long-acting 50–100 24 metoprololCarvedilol Selective alpha- and 6.25–50 7–10 nonselective beta- blockers

* Seen only at low dosage.

† Given intravenously for immediate control of supraventricular tachycardia or systemic arterial hypertension.

verapamil and diltiazem, slow the heart rate by decreasing sinus node impulse formation and AV conduction. Therefore, verapamil and diltiazem have some of the same hemody-namic effects as beta-blockers in that they reduce myocardial oxygen demand at rest and during exercise by attenuating heart rate and contractile responses. However, they also increase coronary blood flow, primarily to epicardial regions supplied by severely narrowed coronary arteries.

Nifedipine, a dihydropyridine calcium antagonist, does not decrease impulse formation in the sinus node or delay AV conduction. Therefore, it does not decrease heart rate but may actually increase it. The dihydropyridine calcium antagonists are potent vasodilators, causing coronary artery vasodilatation. Nifedipine, as the prototype dihydropyridine calcium antagonist, dilates coronary arteries, increasing blood flow to the epicardial regions supplied by signifi -cantly narrowed coronary arteries. Amlodipine, a second-generation dihydropyridine, has greater antihypertensive effects and may reduce cardiovascular events independent of its antihypertensive effects.47

In addition to their negative chronotropic effects, the nondihydropyridines also show significant negative inotro-pic effects. Verapamil has a marked negative inotropic effect on the heart and should not be given to patients with clini-

916 c h a p t e r 38

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CH3

OCH3

OCH3

COCH3

OCH3

OOCCH3

CH3OC

CH3

NO2

CH3

H

H

O O

HS

N

H

O

N

CH(CH3)2

CH2CH2N(CH3)2

CH3O

CH2CH2NCH2CH2CH2CCN

Verapamil

Nifedipine Diltiazem

Slow channelinhibition

Ca2+ Antagonists

Verapamildiltiazem

Verapamildiltiazem

Nifedipineverapamildiltiazem

Myocardium

Negativeinotropism

Slowedheart rate

Peripheraland coronaryvasodilatation

Nodal tissue Vasculature

Binding sites of Ca2+

slow channel bockers

Ca2+

Ca2+

Ca2+Ca2+

Ca2+

Verapamil Diltiazem Nifedipine Slowcalciumchannel

Calcium slow channelblockers produce relaxationof vascular smooth muscleby reducing influx of calciumto the cell

Leak channel SarcoplasmReceptoroperatedchannel

Cistern ofsarcoplasmic

reticulumSarcolemma

Voltage operatedchannel

Mitochondria Thickfilament

Crossbridges

Thinfilament

Z Band Transverse(T) Tubule

Ca-calmodulin

Myosin lightchain kinase

A B

CFIGURE 38.3. (A) The chemical structures for selected slow calcium channel antagonists currently available. (B) The cellular sites of actionfor the slow calcium channel antagonists. (C) The location and type of effect produced by each of the slow calcium channel antagonists.

cally important congestive heart failure (CHF). Diltiazem has a lesser negative inotropic effect, but it should be given very carefully to patients with CHF. Great care should be used in combining diltiazem with another negative inotropic agent, such as a beta-blocker, in the patient with clinically impor-tant CHF. Nifedipine may be given with relative safety to patients with important CHF. Its negative inotropic effect is masked by its ability to reduce systemic vascular resistance,

which enables the heart to contract more effectively against a reduced afterload. As noted previously, beta-blockers are used today in the treatment of selected patients with severe CHF, given in very small and slowly increasing doses.

Each of the slow calcium channel antagonists has impor-tant side effects (Table 38.9). With nifedipine administration, many patients describe a flushing sensation, dizziness, and palpitations, which are consequences of its systemic vasodi-

m e dic a l t r e at m e n t of s ta b l e a ng i n a 917

TABLE 38.6. Selected prototype slow calcium channel blockers

TherapeuticDosage Onset of actionplasma

Oral IV Oral IV concentration Metabolism Excretion

Diltiazem 30–90 μg 75–150 μg/kg >30 min >10 min 50–200 ng/mL Deacetylation 60% fecal (10–20 mg) N-Demethylation O-DemethylationNifedipine 10–40 mg 5–15 μg/kg >20 min >5 min 25–100 ng/mL Alpha- 20–40% fecal

(dihydropyridine q 6–8 h (3 min SL) hydroxycarboxylic 50–80% renalcalcium acid and alpha-antagonist) lactone with no

known activityVerapamil 80–120 mg 150 μg/kg >30 min >5 min <100 ng/mL N-dealkylation 15% fecal q 6–12 h (10–20 mg) N-demethylation 70% renal Major hepatic first- pass effect

SL, sublingual.

TABLE 38.7. Selected newer slow channel calcium antagonists

Type Dosage Special uses Excretion

Nisoldipine (dihydropyridine) 10 mg PO q 12 h Treat systemic arterial hypertension and angina RenalFelodipine (dihydropyridine) 5–10 mg PO q 24 h Treat systemic arterial hypertension and angina RenalNicardipine (dihydropyridine) 20–40 mg PO t.i.d. Treat systemic arterial hypertension and angina RenalNimodipine (dihydropyridine) 60 mg q 4 h PO for 21 days Reduce cerebral vascular ischemia after Renal subarachnoid hemorrhageIsradipine (dihydropyridine) 2.5 mg PO b.i.d. increasing Hypertension Renal up to 20 mg PO qdAmlodipine (dihydropyridine) 5–10 mg PO qd Systemic arterial hypertension and angina Bile and renalBepridil (Na+ and Ca2+ channel 200 mg PO qd increasing Angina Renal and fecal

blocker) to 400 mg PO qd

A calcium antagonist can be combined with nitrates and a beta-blocker for treatment of the patient who experiences angina at low levels of effort. This combination of pharma-cologic agents may be useful in enabling individual patients to be more active without having angina. Clinically, the safest combination of a beta-blocker with a calcium antago-nist is to use a dihydropyridine calcium antagonist, such as nifedipine. The next safest clinical combination is a beta-blocker and diltiazem. One should initiate combined therapy with a beta-blocker and diltiazem or verapamil using rela-tively small doses of the calcium antagonist and gradually increasing them when the patient’s hemodynamic and clini-cal responses are consistent with the safety of the combined regimen.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors, unlike previ-ously mentioned nitrates, beta-blockers, and calcium channel antagonists, do not diminish the symptoms of stable angina. Growing evidence indicates that they provide significant benefit in specific groups of patients with stable angina. Also, unlike beta-blockers and calcium antagonists, the benefits of blocking the renin-angiotensin system are likely independent

lating effect. Peripheral edema occurs in patients who receive nifedipine (and other dihydropyridine calcium antagonists) and is probably the result of venodilatation. Constipation is the major side effect noted by patients taking verapamil, although symptoms related to CHF, bradycardia, or advanced AV block may also occur. The combination of verapamil with a beta-blocker is particularly potent in reducing heart rate, systemic blood pressure, and contractile state. It should be used with extreme caution in patients with CHF, AV block, hypotension, or bradycardia. Diltiazem is usually the best tolerated of the slow calcium channel antagonists. When side effects occur, they are usually related to bradycardia or increasing CHF. A nondihydropyridine calcium antagonist can be used as an alternative to a beta-blocker for treatment of the patient with stable angina. However, there has been considerable concern about potential adverse effects of the calcium antagonists in patients with coronary heart disease, especially in the patient with acute coronary syndromes, such as unstable angina or acute myocardial infarction (AMI) when relatively short-acting dihydropyridine calcium antag-onists, like nifedipine, are given in doses equaling or greater than 80 mg per day. There are data that suggest an increase in mortality and lack of clinical benefit when this agent is given in larger doses to patients with acute coronary syndromes.48

918 c h a p t e r 38

of their effects on blood pressure. For example, the Trial on Reversing Endothelial Dysfunction (TREND) investigators showed that ACE inhibition with quinapril improved endo-thelial dysfunction in patients who were normotensive and who did not have severe hyperlipidemia or heart failure.49

The Heart Outcomes Prevention Evaluation (HOPE) was a large-scale multicenter (267 hospitals in 19 countries), ran-domized, placebo-controlled trial of ACE inhibitor therapy and vitamin E supplementation in patients at high risk for vascular events.50 Inclusion criteria included age greater than 55 years and evidence of vascular disease (coronary heart disease, stroke, or peripheral vascular disease) or diabetes and one other cardiovascular risk factor. Patients with heart failure, a low left ventricular ejection fraction, current ACE inhibitor or vitamin E therapy, or acute events within the previous 4 weeks were excluded. A total of 9541 qualifying patients were randomized to ramipril (up to 10 mg/day) or placebo and vitamin E (400 IU/day) or placebo, and followed for 4 to 6 years. The primary end point of the study was the composite of cardiovascular death, myocardial infarction (MI), or stroke. Secondary end points included revasculariza-tion and the development of CHF, unstable angina, or com-plications of diabetes.

Although vitamin E therapy was not associated with any significant clinical benefit, ramipril therapy was associated with a highly significant clinical benefit (Fig. 38.4). Compos-ite primary outcome events occurred in 13.9% of the ramipril

group and 17.5% of the placebo-treated group [risk ratio (RR), 0.78; p = .000002]. There was also significant benefit in the individual end points of cardiovascular death (6.0% vs. 8.0%; RR, 0.75; p = .002), MI (9.8% vs. 12.0%; RR, 0.80; p = .0005), stroke (3.3% vs. 4.8%; RR, 0.68; p = .0002), and total mortal-ity (10.3% vs. 12.2%; RR, 0.83, p = .035). There were no dif-ferences between groups in noncardiovascular death (4% vs. 4%; p = NS). From the perspective of the secondary end points, there was no effect of ramipril therapy on the develop-ment of unstable angina, but there was a trend toward fewer heart failure hospitalizations and significantly fewer revas-cularizations (16.0% vs. 18%; RR = 0.85 ; p = .0013).

There was also a striking benefit demonstrated in patients with documented normal left ventricular ejection fractions (n = 4676; mean ejection fraction 59%), with significant reductions in the primary outcome end point (13.6% vs. 18.3%), cardiovascular death (5.0% vs. 7.0%), MI (10.3% vs. 13.5%), stroke (2.9 vs. 4.2%), heart failure (8.3% vs. 10.4%), and revascularization (19.8% vs. 23.8%). In the overall popu-lation, the divergence of the primary end point was present in the first year, and the event curves continued to diverge through year 4. The clinical benefit was noted in virtually all of the major subgroups, including patients with or without cerebrovascular disease, diabetes, hypertension, coronary artery disease, or peripheral vascular disease, and in men or women and in young or old.

Mechanistically, there was only a minor decrease in sys-tolic (−2.17 mm Hg) and diastolic (−3.13 mm Hg) blood pres-sure, and the investigators speculated that although there was a strong relationship between clinical events and sys-tolic blood pressure (but not diastolic blood pressure), the primary benefits of ramipril therapy were vascular rather than a blood pressure-lowering effect. In this population, the number of treated patients (4 years of therapy) needed to prevent one primary clinical event was six; treating 1000 patients would prevent 170 adverse clinical events.

The HOPE study provides strong evidence that in patients at risk for vascular events, ACE inhibitor therapy with ramipril significantly reduces cardiovascular death, MI, stroke, heart failure, and revascularization, even in patients

0.20

0.15

0.10

0.05

0.00

Pro

port

ion

of p

atie

nts

Days of follow-up

p < .0001

0 500 1000 1500

PlaceboRamipril

FIGURE 38.4. Kaplan-Meier estimates of the composite outcome of myocardial infarction, stroke, or death from cardiovascular causes in the ramipril group and the placebo group. The relative risk of the composite outcome in the ramipril group was 0.78 (95% confidence interval, 0.70 to 0.86).

TABLE 38.8. Clinical indications for administration of slow calcium channel antagonists to patients with stable angina

Treat the patient with chest pain at a relatively low level of exercise or stress; a calcium antagonist can be used alone or in combination with nitrates and/or a beta-blocker*

Treat the patient with systemic arterial hypertensionTreat the patient with atrial arrhythmias†Treat the patient with exercise-induced ventricular tachycardia‡

* The safest combination of a calcium antagonist with a beta-blocker is with a dihydropyridine calcium antagonist, such as nifedipine. Verapamil and a beta-blocker given together may lead to bradycardia, hypotension, congestive heart failure, or atrioventricular block. Diltiazem and a beta-blocker may lead to similar clinical problems. Therefore, verapamil and diltiazem should be used with great caution when combined with a beta-blocker.

† Verapamil may convert paroxysmal supraventricular tachycardia to sinus rhythm when given intravenously, and verapamil or diltiazem may prevent its recurrence and/or control the ventricular rate in patients in whom the arrhythmia recurs. Verapamil and diltiazem help to control the ventricular rate in the patient with an atrial arrhythmia, such as atrial fibrillation or atrial flutter. Nifedipine has no protective effect against atrial arrhythmias.

‡ The slow calcium channel antagonists may prevent exercise-induced ventricular tachycardia.

TABLE 38.9. Side effects of slow calcium channel antagonists

Verapamil or diltiazem Nifedipine

Marked bradycardia Flushing sensationHypotension DizzinessConstipation HypotensionCongestive heart failure Peripheral edemaSkin rash TachycardiaHeart block Skin rash

m e dic a l t r e at m e n t of s ta b l e a ng i n a 919

with documented normal left ventricular ejection fractions. Vitamin E therapy did not appear to be beneficial.

The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) was a study of 13,655 patients with stable coronary artery disease (CAD) but with no apparent heart failure, including 64% with a previous MI, 61% with angiographic evidence of CAD, 55% with prior coronary revascularization, and 5% with only a positive stress test.51 The primary end point was cardiovas-cular death, MI, or cardiac arrest, determined over a mean follow-up of 4.2 years. Primary end-point events occurred in 10% of placebo-treated patients and 8% of perindopril-treated patients (p = .003). The number needed to treat (NNT) to prevent one event over 4 years was approximately 50 patients. Combined with the HOPE trial, this study strengthened the role of ACE inhibition in patients with CAD.

The Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) study was designed to assess the efficacy of the addition of an ACE inhibitor therapy in patients with stable CAD and normal or slightly reduced left ventricle (LV) function.52 A total of 8290 patients were included in this double-blind, randomized placebo-controlled trial, which compared trandolapril (n = 4158, target dose 4 mg/day) to placebo (n = 4132). Baseline therapy included lipid-lowering therapy in 70% and prior coronary revascular-ization in 72%. The incidence of the primary end point (the composite of cardiovascular death, MI, or revascularization) was 21.9% in the trandolapril group and 22.5% in the placebo group (p = NS) over a median follow-up of 4.8 years. Thus, PEACE showed that the benefits of ACE inhibitors noted in studies of higher-risk patients, such as HOPE and EUROPA, do not necessarily extend into a lower-risk population. Of note, the event rate in the placebo arm of PEACE was lower than that in the ACE inhibitor arms of HOPE and EUROPA. The ACE inhibitors appear to clearly play an important role in the care of some patients with stable angina. Defining the exact extent of that role and the exact subpopulation that can most benefit remains a task for the future.

Platelet Antagonists

When endothelial injury occurs, platelets aggregate after attaching to the subendothelial collagen and other matrix proteins exposed by the endothelial injury. Platelet aggrega-tion may mechanically obstruct severely narrowed coronary arteries and is associated with the accumulation of media-tors that promote further platelet aggregation and dynamic vasoconstriction, including thromboxane A2, serotonin, thrombin, platelet-activating factor, adenosine diphosphate, oxygen-derived free radicals, tissue factor, and endothelin.

Aspirin

In patients at increased risk for MI with known or suspected CAD, this risk may be reduced by the administration of aspirin.53–56 Aspirin is an inhibitor of platelet and endothelial cyclooxygenase (COX-1 and -2), and thus reduces platelet thromboxane and endothelial cell prostacyclin formation (Fig. 38.5). Its effect on platelet cyclooxygenase is irreversible and persists for the lifetime of exposed platelets—approxi-

mately 11 days. With initial therapy, higher doses of aspirin are required to decrease endothelial cell cyclooxygenase activity; therefore, low-dose aspirin tends to reduce throm-boxane more than prostacyclin concentration, but chronic administration of aspirin, even in a low dose, may reduce prostacyclin concentrations as well. Inhibiting release of thromboxane A2 also attenuates platelet aggregation in vivo. Aspirin’s weaker effect, to reduce COX-2 activity, may poten-tially reduce inflammation, and at least some of its beneficial effects may be the result of its decreasing the vulnerability of unstable atherosclerotic plaques by its antiinflammatory effects.

Much of the support for the routine use of aspirin in secondary prevention comes from the Antithrombotic Trial-ists Meta-Analyses. The first meta-analysis (the Antiplatelet Trialists Collaboration), published in 1994, and including clinical trials up through 1990, demonstrated that oral anti-platelet therapy (primary aspirin) was effective in preventing recurrent events across a wide range of atherosclerotic vas-cular disease, primarily coronary and cerebrovascular.57–59 Amore recent and more comprehensive analysis was under-taken, involving trials up through 1997, with additional focus on stroke and peripheral arterial disease, and published in 2002.60 Overall, antiplatelet therapy (primarily aspirin) reduced the incidence of any serious vascular event by one quarter, of nonfatal MI by one third, of nonfatal stroke by

Arachidonic acid

PGG2

PGD2, PDE2 PGH2

PGG2 peroxidase

Decreaseinflammation

Aspirin

↓ Prostacyclin

PGD2 = The major prostaglandin produced by mast cells. Its effects include vasodilatation and contraction of nonvascular smooth muscle.PGE2 = An important prostaglandin having many effects. May cause smooth muscle to either contract or relax.PGG2 = A prostaglandin cyclic endoperoxide, an unstable intermediate.PGH2 = A prostaglandin cyclic endoperoxide formed from PGG2. It is an unstable intermediate and can be converted to several important prostaglandins and thromboxanes.

↓ Thromboxane A2

Thromboxane A2 synthesisProstacyclin synthase

Isomerase(s) or nonenzymatic

FIGURE 38.5. The scheme for the synthesis of thromboxane A2

(TXA2) and prostacyclin (PGI2) from arachidonic acid in platelets and endothelial cells. Aspirin’s inhibitory effect is at the cyclooxy-genase step, where it inhibits this enzyme and thereby diminishes the synthesis of both TXA2 and prostacyclin. TXA2 synthesis inhib-itors interfere with the conversion of PGH2 to TXA2 through TXA2

synthase. TXA2 receptor antagonists simply antagonize the effects of TXA2 on platelets and vascular tissue.

92 0 c h a p t e r 38

one quarter, and vascular mortality by one sixth. The abso-lute reduction in serious vascular events was 36 per 1000 treated for 2 years with previous stroke or transient ischemic attack (TIA). In 21 trials of patients with stroke or TIA, anti-platelet therapy reduced vascular events from 21.4% with control to 17.8%.

The amount of aspirin required to protect patients is not well established. In the meta-analysis above, aspirin doses of 75 to 150 mg daily were at least as effective as higher doses. The effect of doses less than 75mg is less certain. There was no good evidence to support the hypothesis that doses of aspirin ≥1000 mg daily might be preferable in patients at high risk of stroke. A more recent trial (not included in the meta-analysis) supports this. The Aspirin and Carotid Endarterec-tomy Trial showed that in patients undergoing carotid endarterectomy, the composite outcome of MI stroke or death was significantly lower among patients taking 81 or 325 mg of aspirin versus those taking 625 to 1300 mg.61

The Harvard Physicians’ Study suggested that one aspirin every other day reduced the risk for MI in male physicians believed to be at increased risk. However, a British study in which one aspirin per day was administered failed to show protection against the development of MI.54,56 Administra-tion of aspirin to patients after MI reduces the risk of recur-rent infarction and death, especially in patients with non–Q-wave infarcts.53 Although the optimal protective dose of aspirin in patients with CAD is not known, many physi-cians recommend administration of one 325-mg aspirin every other day to one aspirin every day in individuals believed to be at risk for future coronary events. The chronic administration of aspirin, even at a low dose, may decrease vascular prostacyclin concentration. Theoretically, this may be disadvantageous over time, as prostacyclin is an endoge-nous endothelial vasodilator and an inhibitor of platelet aggregation. However, no adverse clinical consequence has been demonstrated.

The authors recommend one aspirin every other day to one aspirin every day in patients believed to be at increased risk for future coronary events and in whom there is no contraindication. Administration of aspirin with consequent cyclooxygenase inhibition and reduction in prostacyclin con-centration may be associated with a reduction in renal blood flow and a rise in the serum blood urea nitrogen and creati-nine. Nonsteroidal antiinflammatory agents that are cyclo-oxygenase inhibitors may also cause a reduction of renal blood flow and a decline in renal function. Periodic measure-ments of blood urea nitrogen and creatinine concentrations are advised once aspirin therapy is begun. There is a risk for gastritis and gastrointestinal ulceration and bleeding when aspirin is administered, and some patients develop asthma (Table 38.10). Therefore, patients should be selected and fol-lowed carefully with aspirin therapy.

Thienopyridines

Another class of antiplatelet agents that may be beneficial in patients with stable angina are the thienopyridines. Ticlopi-dine and clopidogrel, the most widely used thienopyridines, act to inhibit the platelet 2-methylthio–adenosine diphos-phate (ADP)-binding receptor.62–69 In response to other stimuli whose actions may be mediated in part through ADP released

from endogenous platelet granules, thienopyridines also blunt platelet aggregation. Thienopyridines also inhibit platelet aggregation in response to shear stress, and deaggre-gate platelet thrombus that has already formed. It is generally believed that thienopyridines are biotransformed and acti-vated in the liver; biotransformation of the thienopyridines by the hepatic CP450 system has been well documented, and plasma levels of the parent drug are not detectable 2 hours after oral administration. It has been suggested that both ticlopidine and clopidogrel can interfere with in vitro ADP-induced aggregation of washed human platelets; thus, bio-transformation may not be a necessary step.69 This effect was not noted when either plasma or albumin was present. Regardless of the exact mechanism, thienopyridines produce a permanent inhibition of the low-affinity ADP receptor, and platelets exposed to thienopyridines are irreversibly inhib-ited for their lifetime (8 to 10 days).

The onset of action of ticlopidine is about 48 to 72 hours, and it takes about 5 to 6 days to achieve steady-state levels of platelet inhibition. Ticlopidine has also been shown to reduce fibrinogen concentrations and blood viscosity and increases the filterability of whole blood and red blood cells. Ticlopidine is metabolized in the liver. Adverse effects of ticlopidine include neutropenia, rash, diarrhea, and, rarely, thrombotic thrombocytopenic purpura (TTP).64

Clopidogrel bisulfate is a thienopyridine derivative. As compared to ticlopidine, the antiplatelet effects of clopido-grel appear somewhat more rapidly, particularly with oral loading. Clopidogrel is rapidly absorbed after oral administra-tion, reaching peak plasma concentrations approximately 1 hour after an oral dose. Steady-state concentrations are reached after approximately 3 days of consecutive dosing. Food or antacids do not appear to interfere with its absorp-tion or bioavailability. Both clopidogrel and its primary metabolite (a carboxylic acid derivative) are highly protein bound (in vitro binding to albumin of 98% and 94%, respec-tively). The drug is well absorbed in the elderly and has comparable pharmacodynamic effects in the elderly as in younger patients. Evaluation of the pharmacodynamic effects of clopidogrel has shown significant inhibition of platelet function within 2 hours of a 400 mg dose, an effect that per-sists for up to 48 hours. With repeated oral daily doses of 50 to 100 mg, a significant antiplatelet effect is measurable at 48 hours, and reaches steady state 4 to 7 days after initiating therapy. Dose ranging studies have shown that a clopidogrel dose of 75 mg/day provides a similar degree of platelet inhibi-tion to that achieved with 250 mg b.i.d. of ticlopidine. The side effects of clopidogrel are the same or even milder than those seen with aspirin, and much less frequent than with ticlopidine. The much lower frequency of TTP and bone

TABLE 38.10. Potential side effects of aspirin

GastritisStomach or gastrointestinal ulcerationGastrointestinal bleedingEasy bruising and bleeding with minor traumaAsthmaDecline in renal functionThrombocytopenia

m e dic a l t r e at m e n t of s ta b l e a ng i n a 921

marrow toxicity, even over an extended period of follow-up, is a major advantage of clopidogrel over ticlopidine.62

No major trials have yet been completed on the efficacy of ticlodipine in the setting of stable angina. The effect of this drug, therefore, must be extrapolated using trials in stroke patients with risk factors similar to those with stable angina. Two large studies have examined the utility of ticlop-idine in patients with cerebrovascular disease. The Canadian American Ticlopidine Study (CATS) trial compared ticlopi-dine with placebo in patients with a history of recent stroke.70

The primary end point was the composite of ischemic stroke, MI, or vascular death. The placebo group had a primary event greater than the ticlopidine group [relative risk reduction (RRR), 23.3%; p = .02]. The Ticlopidine Aspirin Stroke Study (TASS) trial compared ticlopidine with aspirin in patients with a history of a recent stroke precursor or minor stroke within the past 3 months.71 The primary end point in this trial was the composite of nonfatal stroke and all-cause mor-tality. The aspirin group had a greater primary event rate than the ticlopidine (RRR, 12%; p = .048).

The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a large-scale randomized trial of the safety and efficacy of clopidogrel (75 mg/day) versus aspirin (325 mg/day) in 19,185 patients with atheroscle-rotic vascular disease followed for up to 3 years.72 The study population included patients with recent ischemic stroke (within 6 months), recent myocardial infarction (within 35 days), or symptomatic peripheral arterial disease. The primary end point was the composite incidence of stroke (fatal and

nonfatal), MI (fatal and nonfatal), and other vascular death. At a mean follow-up of 1.9 years, the clopidogrel group had significantly fewer composite first events (5.32% per year risk vs. 5.83% per year with aspirin; RRR, 8.7%; p = .043) (Fig. 38.6). The outcome event most dramatically reduced by clopidogrel therapy was MI. There were no major differences between the aspirin and clopidogrel groups in terms of safety. The incidence of significant neutropenia was 0.10% in the clopidogrel group and 0.17% in the aspirin group. When patients with coronary disease and either concomitant cere-brovascular disease or peripheral vascular disease were exam-ined, there was striking superiority of clopidogrel in reducing outcome events in this population (RRR, 22.7%). Mechanisti-cally, an important factor may be the key role that ADP plays in shear-induced platelet aggregation. In peripheral vascular disease and CAD plus disease in other vascular beds, there is a greater atherosclerotic burden, more shear forces, and, prob-ably, a more important role for ADP-induced platelet activa-tion/aggregation. Additional analyses of the CAPRIE cohort have documented the significant benefit of clopidogrel over aspirin in patients with a prior history of coronary artery bypass graft (CABG) and patients with diabetes, and the ben-efits of clopidogrel over aspirin in preventing not only initial events (the primary CAPRIE analysis) but also recurrent and total vascular events as well.73–75

The Clopidogrel in Unstable Angina to Prevent Recur-rent Ischemic Events (CURE) trial was a multicenter, ran-domized, double-blind, placebo-controlled study comparing combination therapy with aspirin and clopidogrel versus

R = H TiclopidineR = CO2CH3 Clopidogrel

Relative-risk reduction (%)

Stroke

MI

PAD

All patients

–40 –30 –20 –10 0 10 20 30 40Clopidogrel betterAspirin better

20

15

10

5

0

Cum

ulat

ive

risk

(%)

0 3 6 9 12 15 18 21 24 27 30 33 36Time since randomization (months)

Aspirin

Clopidogrel

p = 0.043

Patientsat risk

A:C:

9586 9190 8087 6139 3979 2143 542539217040536160813192479599A B

C

R H

N

ClS

FIGURE 38.6. (A) The chemical struc-ture for ticlopidine and its analogue clop-idogrel. (B) The slight benefit of clopidogrel over aspirin in the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial in reducing future myocardial infarction, stroke, and vascu-lar death. (C) The influence of aspirin or clopidogrel in the CAPRIE trial by future event. PAD, peripheral artery disease.

92 2 c h a p t e r 38

aspirin alone in patients with acute coronary syndromes.76 Atotal of 12,562 patients with unstable angina or non–Q-wave MI (within 24 hours of their last episode of pain) received acetylsalicylic acid (ASA) 75 to 325 mg and then were ran-domized to clopidogrel (300 mg load followed by 75 mg daily) or placebo for 3 months to 1 year. The primary end point was a composite of cardiovascular (CV) death, MI, or stroke. The main safety end points were major bleeding (disabling or symptomatic intracranial or intraocular bleeding; or transfu-sion of more than 2 units) and life-threatening bleeding [hemoglobin (Hgb) decrease of >5 g/dL, hypotension requiring inotropes, bleeding requiring surgery or transfusion of >4units of blood, or intracranial bleeding].

Seventy-five percent of the patients enrolled in CURE had unstable angina; 25% had an elevated enzyme or tropo-nin level; 94% had an abnormal electrocardiogram (ECG); and half had ST-segment deviation. Approximately 30% of the patients underwent revascularization; the mean follow-up was 9 months. Treatment with the combination of clopi-dogrel and ASA was associated with a 20% relative reduction in the primary end point of CV death, MI, or stroke, largely driven by a 23% relative reduction in the incidence of MI. Differences in the other components of the primary end point (CV death, stroke, non-CV death) failed to reach statis-tical significance. The curves for the primary end point began to diverge very early, favoring clopidogrel (within the first few hours). At 24 hours, a 20% relative reduction in the composite of death, MI, and stroke was also noted. The ben-efits of clopidogrel were present across all major subgroups: patients with and without major ST-segment deviation, enzyme or troponin elevation, or prior and subsequent revas-cularization.77 Benefits were also noted in composite events with long-term therapy in addition to in-hospital benefit.Although there was a 34% excess of major bleeding in the clopidogrel arm, there was no significant excess of life-threatening bleeding with combination therapy.

The promising results of the CURE and CAPRIE trials are a strong argument for the use of clopidogrel as an effec-tive tool in the secondary prevention of atherosclerotic disease. The CURE trial assessed the therapeutic role of clopidogrel, in conjunction with aspirin, immediately fol-lowing an ischemic event (non–ST-elevation MI), whereas the CAPRIE trial analyzed the benefit of clopidogrel over aspirin in patients with recent MI, stroke, or peripheral arte-rial disease. These two trials of secondary prevention beg the question of the role of clopidogrel in primary prevention of cardiovascular disease in those patients with a high risk for

cardiovascular disease or in those patients with a remote history of cardiovascular disease. The clopidogrel for high atherothrombotic risk and ischemic stabilization, manage-ment, and avoidance (CHARISMA) trial was designed to help address those issues.

In the CHARISMA trial, 15,603 patients with either clinically evident cardiovascular disease or multiple risk factors for cardiovascular disease were randomized to receive either clopidogrel and low-dose aspirin or placebo plus low-dose aspirin.78 The patients were then followed for a median of 28 months, with assessment of the primary efficacy end point being a composite of MI, stroke, or death from cardio-vascular causes. This primary end point was not statistically different between the two groups (6.8% with clopidogrel plus aspirin vs. 7.3% with aspirin alone; p = .22) (Table 38.11).

However, a prespecified secondary end point, adding hos-pitalizations to the composite primary end point, did show a moderate significant difference (16.7% with clopidogrel plus aspirin vs. 17.9% with aspirin alone; p = .04). There was no significant increase in the rate of severe bleeding (1.7% with clopidogrel plus aspirin compared to 1.3% with aspirin alone; p = .09). Moderate bleeding (requiring blood transfu-sion) was significantly higher in the clopidogrel group (2.1% vs. 1.3% with aspirin alone; p < .01). Looking further at the subgroups of patients included in the study, there appeared to be benefit in patients with “symptomatic atherothrombo-sis” and a suggestion of harm in patients with only multiple risk factors and no manifest disease (Fig. 38.7). “Symptom-atic atherothrombosis” was defined as those patients with documented coronary disease (n = 12,153). In these secondary prevention patients, the primary end point was significantly reduced with clopidogrel plus aspirin (6.9% vs. 7.9% with aspirin alone; p = .046). However, in the 3248 patients with only multiple risk factors and no documented cardiovascular disease (a primary prevention group), there was an increase in the primary end point with clopidogrel plus aspirin (5.4% vs. 3.8% with aspirin alone; p = .04) (Table 38.12). Probably, the most surprising aspect to this finding was in the diabetic population, which would otherwise be regarded as having a coronary artery disease equivalent. Why there should be any potential hazard in this group is completely unknown.

The major message from the CHARISMA trial seems to be that clopidogrel plus aspirin is no better than aspirin alone for primary prevention, even in patients with diabetes. For secondary prevention (such as patients with stable CAD), the message is more ambiguous since this is a secondary sub-group analysis. Clopidogrel plus aspirin appears to provide

TABLE 38.11. End points in the CHARISMA trial

Clopidogrel + aspirin Placebo + aspirinEnd point (n = 7802), n (%) (n = 7801), n (%) Relative risk p value

Primary end point 534 (6.8) 573 (7.3) 0.93 .22Death from any cause 371 (4.8) 374 (4.8) 0.99 .90Death from any cardiovascular cause 238 (3.1) 229 (2.9) 1.04 .68MI (nonfatal) 147 (1.9) 159 (2.0) 0.92 .48Ischemic stroke (nonfatal) 132 (1.7) 160 (2.1) 0.82 .10Stroke (nonfatal) 149 (1.9) 185 (2.4) 0.80 .05Secondary efficacy end point* 1301 (16.7) 1395 (17.9) 0.92 .04Hospitalization for unstable angina, 866 (11.1) 957 (12.3) 0.90 .02

TIA, or revascularization

m e dic a l t r e at m e n t of s ta b l e a ng i n a 92 3

longer term benefit over aspirin alone in patients with estab-lished disease. This finding, however, will have to be pro-spectively evaluated if we are to have any hope of risk-stratifying patients for optimal use of long-term combi-nation therapy.

Oral IIb/IIIa Antagonists

There have been five large randomized trials of oral IIb/IIIa antagonists in patients with atherosclerotic disease: Evalua-tion of Oral Xemilofiban in Controlling Thrombotic Events (EXCITE) (7232 patients undergoing coronary intervention); orbofiban in patients with unstable coronary syndromes/thrombolysis in myocardial ischemia (OPUS/TIMI) 16 (10,288 patients following acute coronary syndromes); Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) (9169 patients following acute coronary syndromes); 2nd SYMPHONY (6637 patients following acute coronary syn-dromes); and blockage of glycoprotein IIb/IIIa to avoid voscu-lar occlusion (BRAVO) (9190 high-risk patients following coronary event, cerebrovascular events, or with multibed vascular disease).79–82 Despite the fact that these studies all used very powerful antiplatelet agents, all five trials demon-strated a trend toward higher mortality in the IIb/IIIa groups. A recent meta-analysis of four of these studies demonstrated a 37% increase in mortality (p = .001), and a 40% increase in MI at 30 days (p = .002) with active therapy.83 Only one of the five trials, BRAVO, included patients with noncoronary

vascular disease as a primary inclusion criteria. Of the 9190 patients enrolled in BRAVO, 3319 had had a recent cerebro-vascular event (within the prior 5 to 30 days), and 1481 had other peripheral vascular disease, with either concomitant coronary or cerebrovascular disease. Similar to the overall population, these subgroups showed a trend toward increased mortality with no significant clinical benefit with lotrafiban, although in all patients with cerebrovascular disease there was a nonsignificant trend favoring lotrafiban. A trial of the oral glycoprotein (GP) IIb/IIIa antagonist chromafiban in patients with peripheral vascular disease was also recently halted prematurely because of safety concerns.

Warfarin

Warfarin and other coumarin anticoagulants inhibit vitamin K-2,3-epoxide reductase in hepatic microsomes, thus inter-fering with hepatic recycling of vitamin K, which is a neces-sary cofactor for the synthesis of specific γ-carboxy-glutamic acid residues.84,85 These particular residues are needed for the posttranslational modification of certain proteins syn-thesized in the hepatocytes, the so-called vitamin K–depen-dent coagulation factors II, VII, IX, and X, and protein C and protein S. Warfarin is water-soluble, is completely absorbed from the gastrointestinal tract, and reaches maximal blood concentrations in 90 minutes. It is metabo-lized by hepatic microsomal enzymes, and is almost totally bound to plasma proteins; consequently, it has a relatively long plasma half-life. Following a dose of warfarin sufficient to completely block hepatic synthesis of vitamin K–depen-dent proteins, each of the involved clotting factors will dis-appear from the blood at a speed inversely proportional to its half-life.

The trials evaluating the role of warfarin in patients with stable angina again require some degree of extrapolation (Table 38.13). The Thrombosis Prevention Trial compared low-intensity warfarin [target international normalized ratio (INR) 1.3–1.8], aspirin (75 mg/day), both, or neither in 5499 men who were at risk for a first MI.86 The primary end point was all ischemic heart disease events, defined as coronary death and fatal and nonfatal MI. Neither warfarin alone nor aspirin alone significantly reduced outcome events; the primary event rates were similar in both groups: 6.5% (8.4% in the placebo group). Primary outcome events, however, were significantly lower with combination therapy: 5.6% overall. Combination therapy was also associated with a small but significant increase in the incidence of hemor-rhagic stroke (0.1%).

A pooled analysis of data from seven randomized trials showed that chronic oral anticoagulant therapy after MI reduced the combined end points of mortality and nonfatal reinfarction by approximately 20% over a 1- to 6-year treat-

CHARISMAPrimary efficacy results (MI/stroke/CV death)

by inclusion criteria category

Population

Documented AT

Coronary

Cerebrovascular

PAD

Multiple RF

Overall population

12,153 0.88 (0.77, 0.998)

5,835

4,320

2,838

3,284

15,603

0.046

0.13

0.09

0.29

0.20

0.22

0.86 (0.71, 1.05)

0.84 (0.69, 1.03)

0.87 (0.67, 1.13)

1.20 (0.91, 1.59)

0.93 (0.83, 1.05)

0.4 0.6 0.8 1.2 1.4 1.6Clopidogrel better Placebo better

N RR (95% Cl) p value

FIGURE 38.7. A summary of the results of the CHARISMA trial with the primary efficacy end points shown by inclusion criteria. Note that in this subgroup analysis, clopidogrel plus aspirin is only significantly superior to aspirin alone in the group with documented atherothrombotic disease. Furthermore, clopidogrel plus aspirin may be more harmful than aspirin alone in those patients with only risk factors for atherothrombotic disease.

TABLE 38.12. Safety end points in the CHARISMA trial

Clopidogrel + aspirin Placebo + aspirinEnd point (n = 7802), n (%) (n = 7801), n (%) Relative risk p value

Severe bleeding 130 (1.7) 104 (1.3) 1.25 .09Fatal bleeding 26 (0.3) 17 (0.2) 1.53 .17Primary intracranial hemorrhage 26 (0.3) 27 (0.3) 0.96 .89Moderate bleeding 164 (2.1) 101 (1.3) 1.62 <.001

9 2 4 c h a p t e r 38

ment period.87–89 A subsequent comprehensive review of 32 trials also suggested that anticoagulant treatment signifi -cantly reduced mortality.90

The beneficial effects of more intense anticoagulant therapy in the postinfarction period have been examined in a number of subsequent studies. The Sixty-Plus Reinfarction Study was limited to patients older than 60 years following an MI who had been treated with oral anticoagulants for at least 6 months prior to enrollment; qualifying patients were then randomized to continue on oral anticoagulant therapy or to have it withdrawn.91 There was a significant reduction in the incidence of reinfarction and stroke in patients ran-domized to continue warfarin therapy. In the Warfarin Rein-farction Study (WARIS), post-MI patients were randomized to warfarin (target INR 2.8–4.8) or placebo.92 There was a highly significant reduction in mortality in the warfarin group (24% relative reduction in the intention-to-treat cohort, and 35% relative reduction in the on-treatment cohort). There was a slightly increased risk of intracranial hemorrhage with warfarin, but this risk was far outweighed by the significant reduction in overall cerebrovascular events. The Anticoagualants in the Secondary Prevention of Events on Coronary Thrombosis (ASPECT) study random-ized patients to higher intensity warfarin therapy (INR 2.8–4.8) or placebo.92 It demonstrated that warfarin was associated with a 40% relative reduction in the incidence of stroke and a greater than 50% relative reduction in the incidence of reinfarction.

More recently, a number of studies have evaluated a variety of intensities of anticoagulation, either alone or in

combination with aspirin in patients with acute coronary syndromes. The WARIS II trial compared warfarin alone (mean INR 2.8), aspirin alone (160 mg/d), or both (mean INR 2.2; aspirin 75 mg/d) in patients with AMI randomized at the time of hospital discharge and followed for 2 years.93 The primary end point was the first occurrence of the composite of all-cause death, nonfatal reinfarction, or thromboembolic stroke; this occurred in 20% of the patients on aspirin alone, 16.7% of those on warfarin alone, and 15% of those on the combination of both drugs. Combination therapy was signifi -cantly superior to aspirin alone (p = .0005), but there was no significant difference between the two warfarin groups. The incidence of major bleeding was 0.15% per year in the aspirin-alone group, 0.58% per year in the warfarin-alone group, and 0.52% per year in the combination group.

Two other recent studies, the Coumadin Aspirin Rein-farction Study (CARS) and the Combined Hemotherapy And Mortality Prevention Study (CHAMP), compared aspirin alone with the combination of aspirin and low-intensity war-farin (lower limit of targeted INR < 2.0). The CARS study demonstrated that low fixed-dose warfarin (1 or 3 mg/d) plus aspirin (80 mg) was no more effective than aspirin alone (160 mg) for long-term treatment of patients post-AMI.94 The CHAMP study evaluated the relative efficacy and safety of aspirin alone (160 mg/d) and the combination of warfarin (INR 1.5–2.5) and aspirin (81 mg/d) in patients following MI in an open-label trial.95 There were no differences between the two groups in total mortality, nonfatal MI, or nonfatal stroke. Again, major bleeding was more common in the com-bination therapy group.

TABLE 38.13. Warfarin trials

Intensity ofanticoagulation

Trial (INR) Warfarin compared to End point Results

Thrombosis 1.3–1.8 Placebo; aspirin Ischemic heart Only combination of aspirin and warfarinPrevention Trial (75 mg/day); disease events significantly reduced end points

combination therapyWarfarin Reinfarction 2.8–4.8 Placebo Death Reduced mortality in warfarin groups,

Study (WARIS) along with 50% relative reduction in incidence of nonfatal reinfarction; a 55%

reduction in incidence of fatal CVA; slightly increased risk of intracranial hemorrhage with warfarin

Secondary Prevention 2.8–4.8 Placebo Stroke; reinfarction Warfarin with 40% relative reduction inof Events on incidence of stroke and a greater thanCoronary 50% relative reduction of incidence ofThrombosis reinfarction(ASPECT)

WARIS II 2.8 Aspirin alone All-cause death, Combination therapy superior to aspirin (160 mg/day), or nonfatal infarction, alone, but no significant differences both (mean INR 2.2; or thromboembolic between the two warfarin groups aspirin 75 mg/day) strokeCARS Aspirin; combination No significant difference; the combination aspirin and warfarin group with significant increase in major (lower limit of bleeding events targeted INR <2.0)Combined Aspirin alone No significant difference; the combination

Hemotherapy and (160 mg/day); group with significant increase in majorMortality combination of bleeding eventsPrevention Study warfarin (INR 1.5(CHAMP) to 2.5) and aspirin

(81 mg/day)

m e dic a l t r e at m e n t of s ta b l e a ng i n a 92 5

The recent American College of Cardiology (ACC)/Amer-ican Heart Association (AHA) guidelines for warfarin therapy cited a recent meta-analysis of 31 randomized trials of oral anticoagulant therapy published between 1960 and 1999.96

These studies all involve patients with CAD treated for ≥3months. When the results are stratified by the intensity of anticoagulation therapy, high-intensity (INR 2.8–4.8) and moderate-intensity (INR 2–3) oral anticoagulation regimens reduced the rates of MI and stroke but increased the risk of bleeding 6.0- to 7.7-fold. In combination with aspirin, low-intensity anticoagulation (INR < 2.0) was not superior to aspirin alone, whereas moderate- to high-intensity oral anti-coagulation and aspirin versus aspirin alone at least showed encouraging trends. There was a modest increase in the bleeding risk associated with the combination.

Risk Factor Reduction

It is very important that patients with known or suspected coronary heart disease and stable angina do everything pos-sible to reduce their risk of future coronary events. Specifi -cally, cessation of smoking, rigorous control of serum cholesterol and low-density lipoprotein (LDL) and triglycer-ides, medical control of systemic arterial hypertension and hyperglycemia, regular exercise, and avoidance of ongoing stressful situations form the hallmark of preventive medical therapy in such individuals.

Smoking Cessation

There are few recommendations that are as clearly or as consistently supported by the literature as the prohibition of smoking in any individual at risk for cardiovascular disease. The deleterious effects of smoking on the cardiovascular system cannot be overstated. Numerous trials have shown that smoking contributes to increases in heart rate, blood pressure, and peripheral vascular resistance.97 Smoking is also prothrombotic, impairs dilation of coronary arteries, and induces a reduction in high-density lipoprotein (HDL). These observed effects coincide well with epidemiologic evi-dence that smoking directly contributes to coronary heart disease and increases mortality.98 Furthermore, the goal of any intervention should be cessation of smoking, as a mere reduction in the amount of smoking in patients at risk seems to provide only marginal benefit.99 The benefits from cessa-tion include a 25% to 50% mortality reduction in those patients who have suffered any MI.100 Multiple intervention modalities should be employed to assist in achieving cessa-tion. These modalities include strong physician advice, a smoking diary, behavioral counseling, buddy-support systems, self-help materials, nicotine replacement therapy, and use of pharmaceutical therapy.97

Hypertension

Like smoking, the negative effects of uncontrolled hyperten-sion on the cardiovascular system cannot be overstated. Although a detailed discussion of hypertension and its effec-tive management is discussed elsewhere in this text, the importance of controlling blood pressure in patients with stable angina should be highlighted.

The World Health Organization estimates that one in every eight deaths worldwide is attributable to hyperten-sion.101 In the United States, previous estimates had 45 million Americans afflicted with this disease, but this population grew significantly with the release of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-7).13

This report defined stage 1 hypertension as a systolic blood pressure ranging from 140 to 159 mm Hg or a diastolic blood pressure ranging from 90 to 99 mm Hg. Stage 2 hypertension was defined as any systolic or diastolic blood pressure greater than the upper boundaries of stage 1. The report went on to define a new category of “prehypertension” that included all individuals with systolic blood pressures between 120 and 139 mm Hg and diastolic blood pressures between 80 and 89 mm Hg. This new category greatly increases the popula-tion of patients that need to be monitored.

Regardless of how one stratifies various degrees of hyper-tension, many studies have shown that blood pressure and risk for cardiovascular disease is consistent and continuous. For most patients, increasing increments of 20 mm Hg in systolic blood pressure or 10 mm Hg in diastolic blood pres-sure were associated with a doubling of risk for cardiovascu-lar disease.102 Furthermore, this effect was seen across a wide range of blood pressure (115/75 to 185/115 mm HG). The JNC-7 report did not recommend particular antihypertensive agents, and recent studies have shown similar outcomes with a variety of agents. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) trial showed that no observed differences were discernible in over 33,000 patients randomized to chlorthalidone, amlodip-ine, or lisinopril.103 Independent-of-the-agent clinical trials have shown that antihypertensive therapy has been associ-ated with a 20% to 25% reduction in MI, 50% reduction in heart failure (HF), and a 35% to 40% reduction in stroke incidence.104

Diet

Although the role of smoking and hypertension is quite clear, the role of diet and cardiovascular risk is more complicated. Many studies support the use of the dietary approaches to stop hypertension (DASH) diet for its beneficial effects on blood pressure.105 This diet is rich in fruits, vegetables, and low-fat dairy foods. It emphasizes fish, poultry, and whole grains, and is reduced in fats, red meat, sweets, and sweet-ened beverages. The long-term cardiovascular effect of this diet has not been well established. More recently, the Mediterranean diet has gained a significant amount of evidence showing its benefit. This diet is characterized by a high intake of vegetables, legumes, fruits, and cereals, moderate to high intake of fish, a low intake of saturated lipids but high intake of unsaturated lipids (mainly in the form of olive oil), low to moderate intake of dairy products, and a moderate intake of ethanol (mainly in the form of wine. This diet has been operationalized, and a scale generated indicates the degree of adherence.106 The Lyon Diet Heart Study was a randomized, single-blind secondary prevention trial that compared a Mediterranean diet to a “prudent Western-type diet.”107 The Mediterranean diet showed a pro-tective effect with a decrease in the rate of cardiac death and

92 6 c h a p t e r 38

nonfatal infarction. Also, the study showed a good degree of compliance with the experimental diet, a finding that was unexpected at the outset of the study. Meta-analyses have shown that this diet in conjunction with nonsmoking and physical activity reduced the mortality from all causes, coro-nary heart disease, cardiovascular disease, and cancer by half.108

Other recent diets (carbohydrate restriction, calorie restriction, fat restriction, macronutrient balance) have shown some modest weight loss benefits but only over a short time course. Also, many of these diets show improve-ment in some cardiac risk factors, but prospective random-ized data are still lacking.109

Lipid-Lowering Therapy

The therapy and strategy for lipid reduction are found else-where in this text along with an explanation of the latest guidelines for various patient risk profiles. The discussion here focuses on those patients with stable angina who by definition represent a high-risk group for cardiovascular events. Three large multicenter clinical trials [the Scandina-vian Simvastatin Survival Study (4S), the West of Scotland Study, and the Cholesterol and Recurrent Events (CARE) trial] have demonstrated the value of 3-hydroxy-3-methylglu-taryl coenzyme A–reductase inhibitors in lowering serum cholesterol and LDL values and reducing the risk of future coronary events in patients with coronary heart disease (CHD) (Fig. 38.8).110–112 These important studies contributed to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines that set the goal of an LDL level below 100 mg/dL in high-risk patients (patients with CHD or CHD equivalents).113 More recent studies have questioned whether high-risk patients might benefit from even more aggressive lipid lowering than those indicated by the ATP III guidelines.

The Heart Protection Study (HPS) evaluated 20,536 patients who were at high risk for cardiovascular events and evaluated whether LDL reductions provided benefit irrespec-tive of initial LDL levels.114 The patients were randomized to 40 mg of simvastatin or placebo, and the primary end points included all-cause mortality, and subcategory analysis included fatal and nonfatal vascular events. As expected, all-cause mortality was significantly reduced among the simvastatin group by 13% (p = .0003). The effects were similar across different subgroups, and no significant differ-ences in adverse events were noted. The subgroup analyses also showed that these benefits also extend to patients regard-less of their baseline LDL values, including those patients at high risk whose LDL values were already below 100 mg/dL (Fig. 38.9).

The lipid half of the PROVE IT/TIMI-22 (Pravastatin or Atorvastatin Evaluation and Infection Therapy) study involved 4162 patients recently hospitalized for acute coronary syn-drome (ACS). They were randomized to 40 mg/day of pravas-tatin or 80 mg/day of atorvastatin (with the assumption that 40 mg/day of pravastatin was equivalent in LDL reduction to 10 mg/day of atorvastatin).115 Although it was originally designed to test for equivalence of the two treatment regi-mens, at a mean follow-up of 24 months the primary event rate (all-cause mortality, MI, unstable angina requiring hos-pitalization, revascularization, or stroke) was 26.3% in the

pravastatin group and 22.4% in the atorvastatin group (p =.005). The LDL in the atorvastatin group (62 mg/dL) was 33 mg/dL below that in the pravastatin (95 mg/dL) group, suggesting that more intensive lipid-lowering regimens in patients post-MI are more beneficial over 2 years (Fig. 38.10).

A similar trial, Reversal of Atherosclerosis with Aggres-sive Lipid Lowering (REVERSAL), was designed to assess the effect of moderate lipid-lowering therapy (40 mg of prava-statin daily) with intense lipid-lowering therapy (80 mg of atorvastatin daily) on the rate of disease progression (assessed by intravascular ultrasonography) in 502 patients with angio-graphically documented coronary artery disease.116 Intravas-cular ultrasonography (IVUS) was performed at baseline and at 18 months; disease progression was measured with volu-metric analysis of reconstructed images. Intensive lipid-lowering therapy was shown to significantly reduce both atherosclerotic progression and adverse clinical outcomes (Fig. 38.11). These benefits appeared to be significantly related to concomitant greater reductions in C-reactive protein (CRP) and atherogenic lipoproteins.

The Z phase of the A to Z trial (Aggrastat to Zocor) was designed to compare early initiation of an intensive statin regimen with delayed initiation of a less intensive regimen in ACS patients.117 The study involved 4497 ACS patients who were randomized to 40 mg/day of simva-statin followed by 80 mg/day thereafter versus placebo for 4 months followed by 20 mg/day of simvastatin. The primary end point (a composite of cardiovascular death, nonfatal MI, readmission for ACS, or stroke) occurred in 14.4% of the early/intensive simvastatin group, and 16.7% of the early placebo/lower dose simvastatin group. No difference in the primary end point was noted in the first 4 months of treatment.

Taken together, the above trials emphasize the need for intensive lipid-lowering goals regardless of when they are initiated. It should also be noted that these findings are spe-cific for patients deemed to be high risk for cardiovascular events (as are those with stable angina). Generalizing the findings to any other groups may be premature at this point.

The importance of lipid lowering can also be highlighted by comparing it to other modalities for treating stable coro-nary disease. For example, Pitt and associates118 studied 341 patients with stable coronary heart disease, relatively normal left ventricular function, asymptomatic or mild-to-moderate angina, and a serum level of LDL cholesterol of at least 115 mg/dL who were referred for percutaneous revasculariza-tion. These investigators randomly assigned the patients either to receive medical treatment with atorvastatin at 80 mg/day (164 patients) or to undergo the recommended per-cutaneous revascularization procedure (angioplasty) followed by the usual care, which could include lipid-lowering treat-ment (177 patients). The aggressive lipid-lowering treatment reduced mean serum LDL concentration to 77 mg/dL. Twenty-two (13%) of these patients had an ischemic event compared with 37 (21%) of the patients who had percutane-ous transluminal coronary angioplasty (PTCA) during an 18-month follow-up. The PTCA-treated patients had a mean serum LDL concentration of 119 mg/dL. The incidence of ischemic events was 36% lower in the atorvastatin group (p = .048), and there was a significantly longer time to first ischemic event (p = .03). The reduction in events was fewer

m e dic a l t r e at m e n t of s ta b l e a ng i n a 927

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Kaplan-Meier analysis of the time to a definite non-fatal myocardial infarction or death from coronary heart dis-

ease, according to treatment group

PlaceboCumulative

eventsNo. at riskPravastatinCumulativeevents

No. at risk

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3293 3230 3167 3099 2714 1241 83

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3302 3256 3215 3162 2807 1330 99

No. AT RiskPlaceboPravastatin

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No. AT RiskPlaceboPravastatin

2078 1956 1857 1739 1634 7542081 1969 1877 1800 1716 819

A B

A

C

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C D

FIGURE 38.8. (A) The influence of simvastatin or placebo on future coronary events, survival, and need for revascularization procedure in the Scandinavian Simvastatin Survival Study (4S) trial. Note the beneficial effect of lipid lowering with simvastatin (Zocor) but also that between 1 and 2 years was required to begin to see the benefi -cial effect from lipid lowering on these variables. (B) The beneficial effect of lipid lowering with the 3–hydroxy-3–methylglutaryl coen-

zyme A reductase inhibitor, pravastatin. Once again, 1 to 2 years of therapy was required to demonstrate the beneficial effect. (C) The reduction in fatal coronary heart disease or nonfatal myocardial infarction (left) and need for coronary bypass surgery or angioplasty (right) with pravastatin or placebo in the Cholesterol and Related Events (CARE) trial. Note that the beneficial results from lipid-lowering therapy required nearly 2 years to be apparent.

PTCAs, CABGs, and hospitalizations for worsening angina. Thus, in patients with stable angina, aggressive lipid-lower-ing therapy appears to be at least as effective as PTCA and usual care in reducing future ischemic events (Fig. 38.12).

Cholesterol-Ester Transfer Protein Inhibitors

Cholesterol-ester transfer protein (CETP) is a lipid transfer protein that is secreted by the liver, and binds primarily to HDL, where it greatly facilitates the transfer of cholesterol esters from HDL to apo-B–containing particles such as very

low density lipoprotein (VLDL), LDL, and chylomicrons, in exchange for triglyceride. When CETP is inhibited, HDL levels rise markedly, as much as 200%. Phase II studies of the CETP inhibitor, torcetrapib, the one furthest along in clinical development, are currently ongoing. A 60-mg dose of torcetrapib is being used in the current clinical trials, looking at both surrogate end points (IMT [intima media thickness], IVUS) and clinical events. An answer should be available in the next few years as to whether HDL-targeted therapy provides comparable or additive benefit to LDL low-ering with statins.

92 8 c h a p t e r 38

A

Baseline feature Statin(n = 10,269)

Placebo(n = 10,267)

Risk ratio and 95% CI

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24% reduction(p <.00001)

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PVD 332

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LDL-C (mg/dL)

<100 285 360

670 881

1087 1365

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Het χ22=0.8

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FIGURE 38.9. (A) The baseline prevalence of various subgroups of patients randomized to simvastatin or placebo as well as their sub-sequent event rate ratio for each subgroup. Note the significant reduction in events across all subgroups. (B) The baseline prevalence of various levels of serum LDL concentrations in patients random-ized to simvastatin or placebo as well as their subsequent event rate ratio for each subgroup. Note the protective benefit of simvastatin extended to those without initial dyslipidemia.

FIGURE 38.10. Kaplan-Meier estimates of the incidence of death from any cause or major cardiovascular event in intensive lipid-lowering therapy with atorvastatin as compared to moderate lipid-lowering therapy with pravastatin. Note the significant reduction of end points in the intensive lipid-lowering therapy group.

A

B

Determination of atheroma area

Change in atheroma area from baseline to follow-up

Baseline Follow-up

Lumen area7.7 mm2

EEM area20.7 mm2

EEM area17.1 mm2Atheroma area

13.0 mm2

Atheroma area7.4 mm2

Lumen area9.8 mm2

Landmarks EEM area Lumen area Atheroma area

FIGURE 38.11. Intravascular ultrasonogra-phy (IVUS) images showing a reduction in atheroma in patients treated with intensive lipid-lowering therapy. (A) Determination of atheroma area by subtracting the lumen area from the area of the external elastic mem-brane. (B) Note in patient randomized to 80 mg of atorvastatin there was a reduction in atheroma area (from 13.0 mm2 to 7.4 mm2)and an increase in lumen are (from 7.7 mm2

to 9.8 mm2).

Metabolic Syndrome

Many definitions of metabolic syndrome have been proposed, but all include the idea that the disorder is characterized by central obesity, dyslipidemia, hypertension, and insulin resistance.119 Approximately 60% of people with metabolic syndrome have obesity as a contributing factor. Only about 10% to 20% of patients with metabolic syndrome actually have impaired fasting glucose levels. In some studies, the risk of cardiovascular death with metabolic syndrome was about 10% at 10 years, and the risk of death, nonfatal MI, or

m e dic a l t r e at m e n t of s ta b l e a ng i n a 92 9

stroke was 18%.120–123 Despite this high degree of risk, current guidelines contain no recommendation for statin therapy in metabolic syndrome patients with LDLs less than 130. Also the same studies showed that increased risk for cardiovascu-lar death was only modestly attenuated after correcting for most of the factors that actually define metabolic syndrome, such as low HDL, high triglycerides, high LDL, and obesity, Thus, the insulin-resistant component of the metabolic syn-drome may be largely responsible for the excess mortality, accounting for about 60% of it.120–123 This has prompted studies looking at the cardiovascular risk-reducing effects of drugs targeted specifically at insulin resistance, thiazoli-dinedione (TZDs) being the most common, but now also the PPAR-α and -γ drugs and pan-PPAR (peroxisome proliferator activated receptor) drugs are in development.

Another interesting aspect regarding the metabolic syn-drome is that there is independent risk associated with all of the individual qualifying criteria. Although three criteria are required to establish the diagnosis, the presence of one or two criteria increases the risk for cardiovascular disease. In the National Health and Nutrition Examination Survey (NHANES), the diagnosis of metabolic syndrome, even adjusting for the risks associated with individual criteria that define it, still confers about a doubling of risk, suggesting that treating these patients entails more than raising HDL, lowering triglyceride and blood pressure, or losing weight.123

These patients may derive additional benefits from treat-ments targeted specifically at insulin resistance. One can view the metabolic syndrome as being associated with end-organ disease. Metabolic syndrome patients consistently have greater carotid IMTs and stiffer vessels than normals; this persists even after correction of the individual risk factors. Electron beam computed tomography (EBCT) in met-abolic syndrome patients demonstrates higher calcium scores than age and gender-matched controls, values that actually fall in the intermediate range between patients without met-abolic syndrome and patients with overt diabetes.123 These observations also support the notion that it is the insulin resistance that has perhaps the most important role in creat-ing end-organ disease.

Weight alone is not the issue. Metabolic syndrome can occur in people who are not overweight; in NHANES III 5% to 10% of the population with a body mass index (BMI) in the 20 to 25 range may have metabolic syndrome. These people may not be obese, but they may have substantial vis-ceral fat; or, in much thinner people, without subcutaneous fat, they may not be making enough adiponectin. In addition, there are probably populations that are lean but have small amounts of visceral fat that happens to be intensely meta-bolically active, resulting in insulin resistance and meta-bolic syndrome. What about losing weight? One can lower the serum CRP, if one loses 20 to 30 pounds. In most people who are really obese, however, weight loss may lower CRP but not to lower-risk levels (<2), since it was probably sub-stantially elevated to start with (frequently in the 5 to 8 range). In obese patients with the metabolic syndrome, weight loss and exercise may be the safest way to lower CRP and blood pressure and improve the lipid profile, but it often is also not enough to affect insulin resistance.

There is also some degree of controversy surrounding the recognition of the disorder and its clinical utility. The Amer-ican Diabetes Association and European Association for the Study of Diabetes have issued a report that calls into ques-tion whether the cluster of cardiovascular risk factors should be designated a disease. Also, the authors report that patients with cardiovascular risk factors should be screened for other risk factors and treated accordingly.124

Miscellaneous

Enhanced External Counterpulsation

Enhanced external counterpulsation (EECP) has been used in the therapy for stable angina for over two decades. It was first proposed in the 1950s as a noninvasive means of increas-ing diastolic and coronary perfusion pressure.125 It works in a similar fashion to the more invasive intraaortic balloon pumps. The procedure employs sequential inflation and deflation of compressible cuffs wrapped around the patient’s calves, lower thighs, and upper thighs. The pressure from these cuffs is transmitted to the arteries during diastole and augments diastolic aortic pressure and consequently increases coronary perfusion pressure. However, it differs from inva-sive balloon pumping in that there is no unloading effect. Moreover, the external counterpulsation is not as effective in increasing systemic diastolic blood pressure in patients with extensive peripheral arterial disease. Microprocessor-interpreted signals coordinate the inflation and deflation of the cuffs with the cardiac cycle.126 Patients typically are treated for 1 hour daily for a total of 35 hours over 7 weeks.

Despite its long history, the evidence for safety and effi -cacy of EECP is largely based on case series. The Multicenter Study of Enhanced External Counterpulsation (MUST-EECP) trial represents the one large randomized controlled trial evaluating EECP in patients with stable angina. The trial randomized 139 patients with angina, documented CAD, and positive exercise treadmill tests to EECP or sham inactive counterpulsation for 35 hours.127 The study used exercise duration, time to ST-segment depression, average daily anginal attacks, and nitroglycerin use as its primary end points. It

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Time since randomization (months)FIGURE 38.12. Cumulative incidence of ischemic events in patients with stable angina randomized to atorvastatin or angioplasty. Note benefit in atorvastatin group.

9 3 0 c h a p t e r 38

found that that there was no significant difference with regard to exercise duration or nitroglycerin use. There was, however, a significant increase in time to ST-segment depression and a decrease in the severity and number of anginal attacks in the EECP groups. Similar smaller studies have shown that EECP improved exercise tolerance and reduced myocardial isch-emia by thallium scintigraphy.128 Furthermore, other small studies indicate that EECP may improve systolic function as evaluated by echocardiography.129

The mechanism through which EECP confers benefits is unclear. The increased pressure gradients could open collat-eral circulation in the ischemic heart.130 Even relatively brief exposure of the various arterial beds to augmented blood flow and increased shear forces may increase production of nitric oxide and prostacyclin, both of which serve as vasodilators.131

Hormone Replacement Therapy

Until recently, many physicians recommended the use of hormone replacement therapy (HRT) for all women after menopause. In addition to alleviating any potential meno-pausal symptoms, it was also believed that “replacing” the “lost” estrogen would provide continued protection against heart disease, osteoporosis and subsequent fractures, and a potential improvement in sexual and cognitive function. These beliefs were reinforced by observational data and trials that utilized secondary end points.132,133

The Heart and Estrogen/Progestin Replacement Study (HERS) trial randomized 2763 women with established coronary disease and a mean age of 66.7 years to either combined hormone therapy with conjugated equine estrogens and medroxyprogesterone acetate or placebo.134 The trial fol-lowed the subjects for 4.1 years and noted no significant dif-ferences with regard to the primary outcome—nonfatal MI or death from coronary heart disease. The trial also noted no significant differences with regard to coronary revasculariza-tion, unstable angina, CHF, stroke, TIA, and peripheral vascu-lar disease. It also noted that a lack of benefit in the above end points was in spite of the improved effects seen in lipid pro-files. Finally, the authors underscored the fact that more car-diovascular events occurred in the first year in the hormone group and fewer occurred in years 4 and 5. Given that more thromboembolic events occurred in the hormone group, the authors concluded that they could not recommend HRT for secondary prevention of coronary heart disease.

The combined HRT arm of the Women’s Health Initiative (WHI) was terminated early due to health risks exceeding benefits.135 The estrogen plus progestin arm randomized 16,608 women with an intact uterus and a mean age of 63 years to either combined hormone replacement therapy or placebo. After a mean of 5.2 years of follow-up, the data and safety monitoring board terminated the study as it noted a “global index” of risk exceeded that of benefit. The study estimated a hazard ratio of 1.29 [nominal 95% confidence interval (CI) of 1.02 to 1.63] for CHD for women taking HRT. It also noted that the greatest risk for CHD was in year 1 of therapy [HR (hazard ratio) 1.78] and most of the risk across all years was in nonfatal MI. This effect was noted in spite of the evidence that HRT improved lipid profiles. No differ-ence in overall mortality or CHD deaths was noted. Beyond the finding that estrogen plus progestin increased CHD

events, the study also described an increase risk in stroke (HR = 1.41, CI of 1.07–1.85), pulmonary embolism (2.13, 1.39–3.25), and breast cancer (1.26, 1.00–1.59). The WHI did show benefits from HRT including a reduction in colorectal cancer (0.63, 0.43–0.92) and hip fractures (0.66, 0.45–0.98). The authors noted that these benefits did not outweigh the overall risk to health, and recommended that HRT as described in the study should not be initiated or continued for primary prevention of CHD.

Therefore, the HERS trial indicated no major role for combined HRT in the secondary prevention of CHD, and the WHI trial similarly concluded no role for HRT in primary prevention. These specific studies could not assess the use of estrogen alone, and neither was designed to evaluate the risk in younger women. The WHI estrogen-alone trial was able to address some of these issues.136 The trial randomized 10,739 women ages 50 to 79 with prior hysterectomy to either estrogen or placebo. This trial was also terminated early (after a mean of 6.8 years of follow-up) by the National Insti-tutes of Health (NIH) despite a lack of consensus from the data and safety monitoring board or crossing of any pre-defined stopping boundary. The trial at that point showed that estrogen therapy did not affect the incidence of CHD (0.91, 0.75–1.12), breast cancer (0.77, 0.59–1.01), pulmonary embolus (1.34, 0.87–2.06), or colorectal cancer (1.08, 0.75–1.55). It did show that estrogen therapy increases the risk of stroke (1.39, 1.10–1.77) and decreases the risk of hip fracture (0.61, 0.41–0.91). The NIH after analyzing this information and noting that estrogen therapy would not affect the risk of CHD or breast cancer, but would put the participant at an increased risk for stroke, deemed the increase risk of stroke unacceptable and terminated the study.

The above trials can be summarized as having concluded that estrogen and progestin combination therapy has no role in either the secondary or primary prevention of heart disease. The above evidence also lends credibility to the theory that there is no cardioprotective effect in estrogen-alone therapy. There may be some role for estrogen-alone therapy in younger women but that remains to be elucidated. Patients with stable angina should probably not initiate HRT at this time.

Nonsteroidal Antiinflammatory Drugs and Medications that Inhibit the Cyclooxygenase Enzymes

Nonsteroidal antiinflammatory drugs (NSAIDs) represent a group of medications that inhibit the cyclooxygenase (COX) enzymes that are responsible for the conversion of arachi-donic acid into various prostanoid compounds. As a class, these compounds act as antipyretics, anti-inflammatory agents, analgesics, and inhibitors of platelet activity but to a varying degree. For example, the prostanoid produced by endothelium is a prostacyclin that promotes smooth muscle relaxation, vasodilation, antagonizes platelet aggregation, and retards atherosclerosis. The prostanoid produced by platelets and thromboxane A2 promotes platelet aggregation and vasoconstriction. Inhibition of the COX enzymes that produce these two prostanoids, therefore, can lead to dra-matically different results.

Aspirin was found to provide antithrombotic activity by the irreversible inhibition of the production of thromboxane

m e dic a l t r e at m e n t of s ta b l e a ng i n a 9 31

A2, and thus provide a means for primary and secondary prevention of cardiovascular events. Other NSAIDs were pri-marily used as antipyretics (acetaminophen) and analgesics (ibuprofen, naproxen, etc.). These NSAIDs were effective but often led to problematic gastrointestinal (GI) side effects including bleeding and ulceration. In the 1990s, it was noted that there were two distinct subgroups of the COX enzymes.137

The COX-1 enzyme was noted to be constitutively expressed in many cell types, but the sole cyclooxygenase in platelets. COX-2 was noted to be induced by inflammation in many cell types, and therefore, inhibition of COX-2 would be anti-inflammatory, and in theory, reduce bleeding by not inhibit-ing the COX-1 enzyme in platelets.

The three COX-2 inhibitors (or COXibs) that were approved by the U.S. Food and Drug Administration (FDA) varied in their degree of COX-2 selectivity (rofecoxib > valde-coxib > celecoxib), but all claimed to reduce GI bleeding over traditional NSAIDs. The Celecoxib Long-Term Arthritis Safety Study (CLASS) compared celecoxib to ibuprofen of diclofenac showed a favorable GI side effect profile at 6 months.138 Unfortunately, an evaluation of the trial data at 12 months did not show superiority and showed a possible increase in cardiovascular events.139 The CLASS trial was somewhat confounded by concomitant use of aspirin in some patients. The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial prohibited use of aspirin and showed a reduced incidence of GI side effects with rofecoxib as compared to naproxen.140 The trial also noted a fivefold increase in cardio-vascular events in the rofecoxib group, but this was felt to be a result of naproxen providing some degree of cardiopro-tection. The Adenomatous Polyp Prevention on Vioxx (APPROVe) trial did compare rofecoxib to placebo and was terminated early due to an excess risk of thrombotic cardio-vascular events.141 This finding led to the voluntary removal of rofecoxib from the market by the manufacturer. Similarly, celecoxib showed a small but statistically relevant dose-related increase in a composite cardiovascular end point of death from cardiovascular causes, MI stroke, or heart failure in the Adenoma Prevention with celecoxib (APC) study.142

However, doses of 200 mg per day or less of celecoxib did not appear to increase the risk of vascular events.

More troubling was the Alzheimer’s Disease Anti-Inflam-matory Prevention Trial (ADAPT), which assessed the poten-tial benefits of celecoxib, naproxen, and placebo on the risk of developing Alzheimer’s disease. This trial was halted by the NIH after it was noted that the naproxen group, but not the celecoxib group, had an increase in cardiovascular and cerebrovascular events.143 Valdecoxib was then found by the FDA to have no advantage over other NSAIDs along with an unfavorable risk-to-benefit ratio, and the manufacturer vol-untarily removed it from the market.144 Finally, the FDA recommended that celecoxib and 18 other NSAIDs (aspirin not included) revise their labels to highlight the increased risk of cardiovascular events.144

At this time, the cardiovascular risks of selective COX-2 inhibitors are real, but the extent unclear. The threat may be secondary to partial inhibition of endothelial prostanoids that are anti–thrombotic/atheroprotective or may be due to possible elevations in blood pressure for some of the agents (e.g., valdecoxib).144 Patients with stable angina or with increased cardiovascular risk factors should avoid COX-2 inhibitors, and if nonaspirin NSAIDs are required, the lowest

effective dose and shortest duration of treatment that is effec-tive should be advised.

Other New Therapies

Ranolazine (Ranexa™) is an orally active piperazine derivative that was recently approved by the FDA (January 2006) for use in chronic stable angina. It acts to selectively inhibit the late inward sodium current, and reduces the degree of ischemia-induced sodium and calcium overload in myocardial cells.145

This unique mechanism of action is not dependent on changes in heart rate, blood pressure, or coronary flow. While the exact mechanism of action for ranolazine may not be completely understood, it also acts to inhibit myocardial fatty acid oxida-tion, and perhaps shifts myocardial metabolism to a more efficient glucose-dependent pathway that requires less oxygen for a similar degree of work. Ranolazine has been shown to reduce ischemia both as monotherapy and in combination with other agents.146–149 IN the recently-published ERICA study (Efficay of Ranolazine in Chronic Angina) trial, ranola-zine, in combination with maximal doses of amlodipine, sig-nificantly reduced both the frequency of angina and nitroglycerin consumption – in comparison to placebo, with no significant hemodynamic effects.150,151

Importantly, ranolazine is associated with dose-related prolongation of the QTc, although there have, as yet, been no reports of torsades de pointes. It is metabolized in the liver (via CYP3A) and excreted in the urine. It is contraindicated in patients with hepatic impairment. Ranolazine should not be used concurrently with diltiazem or verapamil, and dose reductions of digoxin and simvastatin may be necessary.

Summary

Figure 38.13 shows selected therapeutic options in the treat-ment of the patient with stable angina. It must be empha-sized that when angina occurs at relatively low levels of effort or stress, or when it limits the lifestyle that a patient wishes to lead while he or she is receiving appropriate medical therapy, the patient should be referred for coronary arteriog-raphy and subsequently for coronary artery revasculariza-tion—angioplasty, with or without stenting; atherectomy; or coronary artery bypass graft surgery, if the coronary anatomy is suitable. The same is true for the patient with objective evidence of myocardial ischemia, including classic ST-segment alteration (usually ST-segment depression but including ST-segment alteration), or reversible alterations in myocardial perfusion or function at low or moderate levels of stress (exercise or other form of stress myocardial scintig-raphy or echocardiography) who is receiving appropriate medical therapy.145–149 Patients with a significant (≥50% luminal diameter narrowing) left main coronary artery ste-nosis and those with significant three-vessel coronary artery disease (≥70% luminal diameter narrowing) and depressed left ventricular function should undergo coronary artery sur-gical bypass revascularization for the purpose of prolonging their survival, in conjunction with active reversal of all pos-sible risk factors, as reviewed previously.150–153

Thus, in addition to acute therapies directed at improving supply/demand mismatch (nitrates, beta-blockers, calcium channel blockers), marked lowering of serum cholesterol and

9 32 c h a p t e r 38

LDL values, the use of antithrombotic therapy with aspirin and/or clopidogrel, and the use of an ACE inhibitor appear to provide substantial clinical protection against future vascu-lar events.

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All patients with stable angina

Patients with angina only atmoderate activity or stress

Patients with angina at low levels of.activity without a crescendo pattern

Nitrates, aspirin, and β-blocker and/or calciumantagonist that limits heart rate–bloodpressure response to exercise and stressand correct all possible risk factors, includingtreating abnormal serum lipid profile

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Relief of angina at moderatelevels of effort or stress

No relief of angina andit interferes withpatients’ lifestyle

Continued medicaltherapy with periodic (8 to10 months) exercise (orstress) tests with perfusionor functional imaging andrefer for coronaryarteriography those whodevelop angina at low levelsof effort or rest and thosewith reversible perfusion orfunctional abnormalities withstress. Periodic evaluation ofC-reactive protein and, inpatient in whom it increases,careful follow-up and repeatstress perfusion functiontesting.

Refer for coronaryarteriography andcoronaryrevascularization

Continued medicaltherapy for those in whomangina resolves and/oroccurs only with highlevels of activity and whodo not have low levelstress, reversibleperfusion, or functionalabnormality. Repeatedstress perfusion orfunctional evaluation at8- to 10- month intervalsand periodic monitoringfor increases in C-reactive protein, andwhen and if they occur,repeat stress perfusionor functional evaluation

Exercise or stressperfusion or functionalevaluation of patientsfor whom symptomsimprove with medicaltherapy

Refer for coronaryarteriography andsubsequent coronaryrevascularization thosepatients who continueto have angina at low-level effort

Refer for coronaryarteriography thosepatients in whomreversible ECG,perfusion, or functionalalterations occur at lowor moderate levels ofstress, indicatingmyocardial ischemia

FIGURE 38.13. Authors’ schematic diagram of therapeutic options for the treatment of the patient with stable angina.

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