Medical Treatment of Stable Angina

3 8 Medical Treatment of Stable Angina James J. Ferguson III, Dipsu D. Patel, and James T. Willerson Nitrates . . . . . . . . . . . . . . . . . . . ...
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Medical Treatment of Stable Angina James J. Ferguson III, Dipsu D. Patel, and James T. Willerson

Nitrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . β-Adrenergic Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . Calcium Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Angiotensin-Converting Enzyme Inhibitors. . . . . . . . . .

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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 coronary 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 delivery 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 profound 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 hospitalization 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 coronary 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 formation while increasing coronary blood flow. The dihydropyridine calcium antagonists do not decrease AV

Platelet Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Risk Factor Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . Miscellaneous. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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conduction and sinus impulse formation but do increase coronary blood flow. • The nondihydropyridines have significant negative inotropic 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 coronary 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 beneficial 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 significantly increase the risk of future vascular events. Patients with stable angina usually have angina with effort, exercise, or emotion; after eating relatively large meals;

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or during other stressful circumstances that increase myocardial oxygen demand by increasing heart rate, contractile 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 myocardial 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 addition, 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 exercise 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.

H2C O NO2

H3C CHCH2CH2ONO H3C

HC O NO2 H2C O NO2 Nitroglycerin (glyceryl trinitrate, nitro-bid nitrostat, others)

H2C H2C O HC O HC O H2C O

HC O NO2 O CH HC O O2N O CH

Heart

Amyl nitrate (isoamyl nitrate)

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NO2 NO2 NO2 NO2

Nitroglycerin dilates large and mediumsized coronary arteries

Decrease in Venous return to the right heart with consequent wall tension demand reduction

With consequent increase in coronary blood flow to subendocardial region

CH2 Erythrityl tetranitrate (cardilate)

CH2 O NO2 O2N O H2C C O2N O H2C CH2 O NO2 Pentaerythritol tetranitrate (pentritol, peritrate, others)

A

Organic nitrates

Systemic circulation

Isosorbide dinitrate (isordil, sorbitrate, others)

Nitroglycerin dilates systemic veins

Systemic veins

Systemic arteries

Nitroprusside

B Nitric oxide (NO) formation Conversion to S-nitrosothiols

Guanylate cyclase

GTP Vascular smooth muscle cell

C

cGMP

Relaxation

FIGURE 38.1. (A) The chemical structures for selected nitrate preparations. (B) Nitroglycerin’s physiologic effects in the heart and in the peripheral venous system. Nitroglycerin dilates large and mediumsized 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 myocardial oxygen demand. (C) The cellular biochemical effects of nitrates that correlate with their properties as coronary artery vasodilators. 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 activation of guanylate cyclase and the cellular increases in cGMP. GTP, guanosine triphosphate.

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m edica l t r e atm en t of sta ble a ngi na TABLE 38.1. Nitrate preparations used in the treatment of angina pectoris Preparation

Dosage

Duration of effect

Frequency of administration

Sublingual nitroglycerin Sublingual or chewable isosorbide dinitrate Oral isosorbide dinitrate (Isordil) Oral isosorbide mononitrate (Ismo) Oral isosorbide mononitrate (Imdur) Oral isosorbide dinitrate (Tembid), longeracting preparation Pentaerythritol tetranitrate (Peritrate) Oral Sustained Sustained-release oral nitroglycerin (Nitro-Bid) Nitroglycerin ointment

0.3–0.5 mg 2.5–10 mg 5–30 mg 10–20 mg 30–60 mg 40 mg

15–30 min 30 min–1 h 2h 24 h 24 h 6–8 h

For individual episodes May be used instead of nitroglycerin Every 2–3 h while patient is awake Daily Daily Every 6–8 h

10–40 mg 80 mg 2.5–6.5 mg

3–4 h 8–10 h 6h

Every 3–4 h Every 8–10 h Every 6 h

Thin film on 1– 2 inches over small area of anterior chest 0.1 mg/h, 0.2 mg/h, 0.4 mg/h 1 puff prn

4–6 h

Every 4–6 h

Approximately 12 h

Every 12–24 h

Few minutes

Prn for chest pain

Nitroglycerin patches (sustained release) Nitroglycerin spray (Nitrolingual)

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 subendocardial region supplied by a severely narrowed coronary artery. Most other coronary vasodilators increase coronary blood flow and oxygen delivery to the epicardium or midmyocardium without directly changing oxygen availability within the subendocardial region itself. The coronary vasodilator 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 longacting and orally administered nitrates, such as isosorbide

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 monophosphate (cGMP) (i.e., vardenafil and tadalafil). This combination 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 exercise (Tables 38.2 to 38.4). Through these effects, selected beta-blockers have been shown in numerous trials to have

TABLE 38.2. Side effects of b-adrenergic antagonists Easy fatigability Insomnia Dizziness or syncope Dyspnea with effort Sexual impotence Bronchospasm Bradycardia Heart block Hypotension More difficult to recognize hypoglycemia in the insulindependent diabetic

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

Agonist hormone β-adrenergic receptor

Prevent development of angina at relatively low heart rate-systolic blood pressure product Treat exercise-induced ventricular arrhythmias Treat systemic arterial hypertension

mortality benefits in patients with hypertension, after myocardial 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 betablockers 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 attenuate bronchial and smooth muscle dilatation and exacerbate bronchospasm. Nonspecific beta-blockers, such as propranolol, reduce heart rate and myocardial contractile state and interfere with bronchial and vascular smooth muscle dilatation. 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. Therefore, 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-

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G protein β α

γ

Adenylate cyclase

GDP

β α

γ

GDP

GDP

β γ α

Cyclic AMP Kinase (Active)

ATP

Kinase (Inactive)

Phosphorylation Contraction of heart muscle 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 contractile force, through the following mechanisms: (1) sympathetic nerve terminals release norepinephrine, which binds to the β-adrenergic 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.

TABLE 38.4. Relative contraindications to the administration of b-adrenergic antagonists Severe congestive heart failure* Marked bradycardia (heart rate 10 min

50–200 ng/mL

Nifedipine (dihydropyridine calcium antagonist)

10–40 mg q 6–8 h

5–15 μg/kg

>20 min

>5 min (3 min SL)

25–100 ng/mL

Verapamil

80–120 mg q 6–12 h

150 μg/kg (10–20 mg)

>30 min

>5 min

5 g/dL, hypotension requiring inotropes, bleeding requiring surgery or transfusion of >4 units of blood, or intracranial bleeding]. Seventy-five percent of the patients enrolled in CURE had unstable angina; 25% had an elevated enzyme or troponin level; 94% had an abnormal electrocardiogram (ECG); and half had ST-segment deviation. Approximately 30% of the patients underwent revascularization; the mean followup was 9 months. Treatment with the combination of clopidogrel 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 statistical 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 benefits of clopidogrel were present across all major subgroups: patients with and without major ST-segment deviation, enzyme or troponin elevation, or prior and subsequent revascularization.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 lifethreatening bleeding with combination therapy. The promising results of the CURE and CAPRIE trials are a strong argument for the use of clopidogrel as an effective tool in the secondary prevention of atherosclerotic disease. The CURE trial assessed the therapeutic role of clopidogrel, in conjunction with aspirin, immediately following 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 arterial 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

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cardiovascular disease or in those patients with a remote history of cardiovascular disease. The clopidogrel for high atherothrombotic risk and ischemic stabilization, management, 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 lowdose 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 cardiovascular 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 hospitalizations 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 transfusion) 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 atherothrombosis” and a suggestion of harm in patients with only multiple risk factors and no manifest disease (Fig. 38.7). “Symptomatic 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 subgroup analysis. Clopidogrel plus aspirin appears to provide

TABLE 38.11. End points in the CHARISMA trial End point

Primary end point Death from any cause Death from any cardiovascular cause MI (nonfatal) Ischemic stroke (nonfatal) Stroke (nonfatal) Secondary efficacy end point* Hospitalization for unstable angina, TIA, or revascularization

Clopidogrel + aspirin (n = 7802), n (%)

534 371 238 147 132 149 1301 866

(6.8) (4.8) (3.1) (1.9) (1.7) (1.9) (16.7) (11.1)

Placebo + aspirin (n = 7801), n (%)

573 374 229 159 160 185 1395 957

(7.3) (4.8) (2.9) (2.0) (2.1) (2.4) (17.9) (12.3)

Relative risk

p value

0.93 0.99 1.04 0.92 0.82 0.80 0.92 0.90

.22 .90 .68 .48 .10 .05 .04 .02

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CHARISMA Primary efficacy results (MI/stroke/CV death) by inclusion criteria category N

Population Documented AT

RR (95% Cl)

p value

12,153 0.88 (0.77, 0.998) 0.046

Coronary

5,835

0.86 (0.71, 1.05)

0.13

Cerebrovascular

4,320

0.84 (0.69, 1.03)

0.09

PAD

2,838

0.87 (0.67, 1.13)

0.29

Multiple RF

3,284

1.20 (0.91, 1.59)

0.20

Overall population

15,603 0.93 (0.83, 1.05)

0.22

0.4 0.6 0.8 Clopidogrel better

1.2 1.4 1.6 Placebo better

vascular disease as a primary inclusion criteria. Of the 9190 patients enrolled in BRAVO, 3319 had had a recent cerebrovascular 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

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.

longer term benefit over aspirin alone in patients with established disease. This finding, however, will have to be prospectively evaluated if we are to have any hope of risk-stratifying patients for optimal use of long-term combination therapy.

Oral IIb/IIIa Antagonists There have been five large randomized trials of oral IIb/IIIa antagonists in patients with atherosclerotic disease: Evaluation 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 syndromes); and blockage of glycoprotein IIb/IIIa to avoid voscular 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 demonstrated 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

Warfarin and other coumarin anticoagulants inhibit vitamin K-2,3-epoxide reductase in hepatic microsomes, thus interfering with hepatic recycling of vitamin K, which is a necessary 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 synthesized in the hepatocytes, the so-called vitamin K–dependent 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 metabolized 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–dependent proteins, each of the involved clotting factors will disappear 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 hemorrhagic 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-

TABLE 38.12. Safety end points in the CHARISMA trial End point

Severe bleeding Fatal bleeding Primary intracranial hemorrhage Moderate bleeding

Clopidogrel + aspirin (n = 7802), n (%)

130 26 26 164

(1.7) (0.3) (0.3) (2.1)

Placebo + aspirin (n = 7801), n (%)

104 17 27 101

(1.3) (0.2) (0.3) (1.3)

Relative risk

p value

1.25 1.53 0.96 1.62

.09 .17 .89

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