American College of Cardiology

BRAUNWALD ET AL., MANAGEMENT OF PATIENTS WITH UNSTABLE ANGINA AND NON-ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION UPDATE
http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm

ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction

A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)

III. Hospital Care

Patients with UA/NSTEMI, recurrent symptoms and/or ECG ST-segment deviations, or positive cardiac markers who are stable hemodynamically should be admitted to an inpatient unit with continuous rhythm monitoring and careful observation for recurrent ischemia (a step-down unit) and managed according to the acute ischemia pathway (Figure 7). Patients with continuing discomfort and/or hemodynamic instability should be hospitalized for at least 24 h in a coronary care unit characterized by a nursing-to-patient ratio sufficient to provide 1) continuous rhythm monitoring, 2) frequent assessment of vital signs and mental status, 3) documented ability to perform defibrillation quickly after the onset of ventricular fibrillation, and 4) adequate staff to perform these functions. Patients should be maintained at that level of care until they have been observed for at least 24 h without any of the following major complications: sustained ventricular tachycardia or fibrillation, sinus tachycardia, atrial fibrillation or flutter, high-degree AV block, sustained hypotension, recurrent ischemia documented by symptoms or ST-segment change, new mechanical defect (ventricular septal defect or MR), or CHF.

Once a patient with documented high-risk ACS is admitted, standard medical therapy is indicated as discussed later. Unless a contraindication exists, these patients should be treated with aspirin (ASA), a beta-blocker, antithrombin therapy, and a GP IIb/IIIa inhibitor. Furthermore, critical decisions are required regarding the angiographic strategy. One option is a routine angiographic approach in which coronary angiography and revascularization are performed unless a contraindication exists. Within this approach, the most common strategy has called for a period of medical stabilization. Some physicians are now taking a more aggressive approach, with coronary angiography and revascularization performed within 24 h of admission; the rationale for the more aggressive approach is the protective effect of carefully administered antithrombin and antiplatelet therapy on procedural outcome. The alternative approach, commonly referred to as the "initially conservative strategy" (see Section III. D), is guided by ischemia, with angiography reserved for patients with recurrent ischemia or a "high-risk" stress test despite medical therapy. Regardless of the angiographic strategy, an assessment of LV function should be strongly considered in patients with documented ischemia because of the imperative to treat patients who have impaired LV function with angiotensin-converting enzyme (ACE) inhibitors (ACEIs) and beta-blockers and, when the coronary anatomy is appropriate (e.g., 3-vessel coronary disease), with CABG (see Section IV). When the coronary angiogram is obtained, a left ventriculogram can be obtained at the same time. When coronary angiography is not scheduled, echocardiography or nuclear ventriculography can be used to evaluate LV function.

A. Anti-Ischemic Therapy

Recommendations for Anti-Ischemic Therapy

Class I

1. Bed rest with continuous ECG monitoring for ischemia and arrhythmia detection in patients with ongoing rest pain. (Level of Evidence: C)
2. NTG, sublingual tablet or spray, followed by intravenous administration, for the immediate relief of ischemia and associated symptoms. (Level of Evidence: C)
3. Supplemental oxygen for patients with cyanosis or respiratory distress; finger pulse oximetry or arterial blood gas determination to confirm adequate arterial oxygen saturation (Sao₂ greater than 90%) and continued need for supplemental oxygen in the presence of hypoxemia. (Level of Evidence: C)
4. Morphine sulfate intravenously when symptoms are not immediately relieved with NTG or when acute pulmonary congestion and/or severe agitation is present. (Level of Evidence: C)
5. A beta-blocker, with the first dose administered intravenously if there is ongoing chest pain, followed by oral administration, in the absence of contraindications. (Level of Evidence: B)
6. In patients with continuing or frequently recurring ischemia when beta-blockers are contraindicated, a nondihydropyridine calcium antagonist (e.g., verapamil or diltiazem) as initial therapy in the absence of severe LV dysfunction or other contraindications. (Level of Evidence: B)
7. An ACEI when hypertension persists despite treatment with NTG and a beta-blocker in patients with LV systolic dysfunction or CHF and in ACS patients with diabetes. (Level of Evidence: B)

Class IIa

1. Oral long-acting calcium antagonists for recurrent ischemia in the absence of contraindications and when beta-blockers and nitrates are fully used. (Level of Evidence: C)
2. An ACEI for all post-ACS patients. (Level of Evidence: B)
3. Intra-aortic balloon pump (IABP) counterpulsation for severe ischemia that is continuing or recurs frequently despite intensive medical therapy or for hemodynamic instability in patients before or after coronary angiography. (Level of Evidence: C)

Class IIb

1. Extended-release form of nondihydropyridine calcium antagonists instead of a beta-blocker. (Level of Evidence: B)
2. Immediate-release dihydropyridine calcium antagonists in the presence of a beta-blocker. (Level of Evidence: B)

Class III

1. NTG or other nitrate within 24 h of sildenafil (Viagra) use. (Level of Evidence: C)
2. Immediate-release dihydropyridine calcium antagonists in the absence of a beta-blocker. (Level of Evidence: A)

The optimal management of UA/NSTEMI has the twin goals of the immediate relief of ischemia and the prevention of serious adverse outcomes (i.e., death or MI/[re]infarction). This is best accomplished with an approach that includes anti-ischemic therapy (Table 10), antiplatelet and antithrombotic therapy (see also Table 14), ongoing risk stratification, and the use of invasive procedures. Patients who are at intermediate or high risk for adverse outcome, including those with ongoing ischemia refractory to initial medical therapy and those with evidence of hemodynamic instability, should if possible be admitted to a critical care environment with ready access to invasive cardiovascular diagnosis and therapy procedures. Ready access is defined as ensured, timely access to a cardiac catheterization laboratory with personnel who have credentials in invasive coronary procedures, as well as to emergency or urgent cardiac surgery, vascular surgery, and cardiac anesthesia ⁽¹³²⁾.

The approach to the achievement of the twin goals described here includes the initiation of pharmacological management and planning of a definitive treatment strategy for the underlying disease process. Most patients are stable at presentation or stabilize after a brief period of intensive pharmacological management and, after appropriate counseling, will be able to participate in the choice of an approach for definitive therapy. A few patients will require prompt triage to emergency or urgent cardiac catheterization and/or the placement of an IABP. Some will prefer the continuation of a medical regimen without angiography. These patients require careful monitoring of the response to initial therapy with noninvasive testing and surveillance for persistent or recurrent ischemia, hemodynamic instability, or other features that may dictate a more invasive approach. Other patients prefer a more invasive strategy that involves early coronary angiography with a view toward revascularization.

1. General Care
The severity of symptoms dictates some of the general care that should be given during the initial treatment. Patients should be placed at bed rest while ischemia is ongoing but can be mobilized to a chair and bedside commode when symptom free. Subsequent activity should not be inappropriately restrictive; instead, it should be focused on the prevention of recurrent symptoms and liberalized as judged appropriate when response to treatment occurs. Patients with cyanosis, respiratory distress, or other high-risk features should receive supplemental oxygen. Adequate arterial oxygen saturation should be confirmed with direct measurement or pulse oximetry. No evidence is available to support the administration of oxygen to all patients with ACS in the absence of signs of respiratory distress or arterial hypoxemia. Oxygen use during initial evaluation should be limited to patients with questionable respiratory status or those with documented hypoxemia, because it consumes resources and evidence for its routine use is lacking. Inhaled oxygen should be administered if the arterial oxygen saturation (Sao₂) declines to less than 90%. Finger pulse oximetry is useful for the continuous monitoring of Sao₂ but is not mandatory in patients who do not appear to be at risk of hypoxia. Patients should undergo continuous ECG monitoring during their ED evaluation and early hospital phase, because sudden, unexpected ventricular fibrillation is the major preventable cause of death in this early period. Furthermore, monitoring for the recurrence of ST-segment shifts provides useful diagnostic and prognostic information, although the system of monitoring for ST-segment shifts must include specific methods intended to provide stable and accurate recordings.

2. Use of Anti-Ischemic Drugs
a. Nitrates
NTG reduces myocardial oxygen demand while enhancing myocardial oxygen delivery. NTG, an endothelium-independent vasodilator, has both peripheral and coronary vascular effects. By dilating the capacitance vessels (i.e., the venous bed), it increases venous pooling to decrease myocardial preload, thereby reducing ventricular wall tension, a determinant of myocardial oxygen consumption (MVO₂). More modest effects on the arterial circulation decrease systolic wall stress (afterload), contributing to further reductions in MVO₂. This decrease in myocardial oxygen demand is in part offset by reflex increases in heart rate and contractility, which counteract the reductions in MVO₂ unless a beta-blocker is concurrently administered. NTG dilates normal and atherosclerotic epicardial coronary arteries as well as smaller arteries that constrict with certain stressors (e.g., cold, mental or physical exercise). With severe atherosclerotic coronary obstruction and with less severely obstructed vessels with endothelial dysfunction, physiological responses to changes in myocardial blood flow are often impaired (i.e., loss of flow-mediated dilation), so maximal dilation does not occur unless a direct-acting vasodilator like NTG is administered. Thus, NTG promotes the dilation of large coronary arteries as well as collateral flow and redistribution of coronary blood flow to ischemic regions. Inhibition of platelet aggregation also occurs with NTG ⁽¹³³⁾, but the clinical significance of this action is not well defined.

Patients whose symptoms are not relieved with three 0.4-mg sublingual NTG tablets or spray taken 5 min apart (Table 11) and the initiation of an intravenous beta-blocker (when there are no contraindications), as well as all nonhypotensive high-risk patients (Table 6), may benefit from intravenous NTG, and such therapy is recommended in the absence of contraindications (i.e., the use of sildenafil [Viagra] within the previous 24 h or hypotension). Sildenafil inhibits the phosphodiesterase (PDE5) that degrades cyclic guanosine monophosphate (cGMP), and cGMP mediates vascular smooth muscle relaxation by nitric oxide. Thus, NTG-mediated vasodilatation is markedly exaggerated and prolonged in the presence of sildenafil. Nitrate use within 24 h after sildenafil or the administration of sildenafil in a patient who has received a nitrate within 24 h has been associated with profound hypotension, MI, and even death ⁽¹³⁴⁾.

Intravenous NTG may be initiated at a rate of 10 mcg per min through continuous infusion with nonabsorbing tubing and increased by 10 mcg per min every 3 to 5 min until some symptom or blood pressure response is noted. If no response is seen at 20 mcg per min, increments of 10 and, later, 20 mcg per min can be used. If symptoms and signs of ischemia are relieved, there is no need to continue to increase the dose to effect a blood pressure response. If symptoms and signs of ischemia are not relieved, the dose should be increased until a blood pressure response is observed. Once a partial blood pressure response is observed, the dosage increase should be reduced and the interval between increments should be lengthened. Side effects include headache and hypotension. Caution should be used when systolic blood pressure falls to less than 110 mm Hg in previously normotensive patients or to greater than 25% below the starting mean arterial blood pressure if hypertension was present. Although recommendations for a maximal dose are not available, a ceiling of 200 mcg per min is commonly used. Prolonged (2 to 4 weeks) infusion at 300 to 400 mcg per h does not increase methemoglobin levels ⁽¹³⁵⁾.

Topical or oral nitrates are acceptable alternatives for patients without ongoing refractory symptoms. Tolerance to the hemodynamic effects of nitrates is dose and duration dependent and typically becomes important after 24 h of continuous therapy with any formulation. Patients who require continued intravenous NTG beyond 24 h may require periodic increases in infusion rate to maintain efficacy. An effort must be made to use non-tolerance-producing nitrate regimens (lower dose and intermittent dosing). When patients have been free of pain and other manifestations of ischemia for 12 to 24 h, an attempt should be made to reduce the dose of intravenous NTG and to switch to oral or topical nitrates. It is not appropriate to continue intravenous NTG in patients who remain free of signs and symptoms of ischemia. When ischemia recurs during continuous intravenous NTG therapy, responsiveness to nitrates can often be restored by increasing the dose and then, after symptoms have been controlled for several hours, attempting to add a nitrate-free interval. This strategy should be pursued as long as symptoms are not adequately controlled. In stabilized patients, intravenous NTG should generally be converted within 24 h to a nonparenteral alternative (Table 11) administered in a non-tolerance-producing regimen to avoid the potential reactivation of symptoms.

Most studies of nitrate treatment in UA have been small and uncontrolled, and there are no randomized, placebo-controlled trials that address either symptom relief or reduction in cardiac events. One small, randomized trial compared intravenous NTG with buccal NTG and found no significant difference in the control of ischemia ⁽¹³⁶⁾. An overview of small studies of NTG in AMI from the prethrombolytic era suggested a 35% reduction in mortality rates ⁽¹³⁷⁾, although both the Fourth International Study of Infarct Survival (ISIS-4) ⁽¹³⁸⁾ and Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico (GISSI-3) ⁽¹³⁹⁾ trials formally tested this hypothesis in patients with suspected AMI and failed to confirm this magnitude of benefit. However, these large trials are confounded by frequent prehospital and hospital use of NTG in the "control" groups. The abrupt cessation of intravenous NTG has been associated with exacerbation of ischemic changes on the ECG ⁽¹⁴⁰⁾, and a graded reduction in the dose of intravenous NTG is advisable.

Thus, the rationale for NTG use in UA is extrapolated from pathophysiological principles and extensive, although uncontrolled, clinical observations ⁽¹³³⁾.

b. Morphine Sulfate
Morphine sulfate (1 to 5 mg intravenously [IV]) is recommended for patients whose symptoms are not relieved after 3 serial sublingual NTG tablets or whose symptoms recur despite adequate anti-ischemic therapy. Unless contraindicated by hypotension or intolerance, morphine may be administered along with intravenous NTG, with careful blood pressure monitoring, and may be repeated every 5 to 30 min as needed to relieve symptoms and maintain patient comfort.

Morphine sulfate has potent analgesic and anxiolytic effects, as well as hemodynamic effects that are potentially beneficial in UA/NSTEMI. No randomized trials have defined the unique contribution of morphine to the initial therapeutic regimen or its optimal administration schedule. Morphine causes venodilation and may produce modest reductions in heart rate (through increased vagal tone) and systolic blood pressure to further reduce myocardial oxygen demand. The major adverse reaction to morphine is an exaggeration of its therapeutic effect, causing hypotension, especially in the presence of volume depletion and/or vasodilator therapy. This reaction usually responds to supine or Trendelenburg positioning or intravenous saline boluses and atropine when accompanied by bradycardia; it rarely requires pressors or naloxone to restore blood pressure. Nausea and vomiting occur in approximately 20% of patients. Respiratory depression is the most serious complication of morphine; severe hypoventilation that requires intubation occurs very rarely in patients with UA/NSTEMI treated with this agent. Naloxone (0.4 to 2.0 mg IV) may be administered for morphine overdose with respiratory and/or circulatory depression. Meperidine hydrochloride can be substituted in patients who are allergic to morphine.

c. Beta-Adrenergic Blockers
Beta-blockers competitively block the effects of catecholamines on cell membrane beta-receptors. Beta1-adrenergic receptors are located primarily in the myocardium; inhibition of catecholamine action at these sites reduces myocardial contractility, sinus node rate, and AV node conduction velocity. Through this action, they blunt the heart rate and contractility responses to chest pain, exertion, and other stimuli. They also decrease systolic blood pressure. All of these effects reduce MVO₂. Beta2-adrenergic receptors are located primarily in vascular and bronchial smooth muscle; the inhibition of catecholamine action at these sites produces vasoconstriction and bronchoconstriction ⁽¹⁴¹⁾. In UA/NSTEMI, the primary benefits of beta-blockers are due to effects on beta1-adrenergic receptors that decrease cardiac work and myocardial oxygen demand. Slowing of the heart rate also has a very favorable effect, acting not only to reduce MVO₂ but also to increase the duration of diastole and diastolic pressure-time, a determinant of coronary flow and collateral flow.

Beta-blockers should be started early in the absence of contraindications. These agents should be administered intravenously followed by oral administration in high-risk patients as well as in patients with ongoing rest pain or orally for intermediate- and low-risk patients (Table 6).

The choice of beta-blocker for an individual patient is based primarily on pharmacokinetic and side effect criteria, as well as on physician familiarity (Table 12). There is no evidence that any member of this class of agents is more effective than another, except that beta-blockers without intrinsic sympathomimetic activity are preferable. The initial choice of agents includes metoprolol, propranolol, or atenolol. Esmolol can be used if an ultrashort-acting agent is required.

Patients with marked first-degree AV block (i.e., ECG PR interval [PR] of greater than 0.24 s), any form of second- or third-degree AV block in the absence of a functioning pacemaker, a history of asthma, or severe LV dysfunction with CHF should not receive beta-blockers on an acute basis ⁽²⁶⁾. Patients with significant sinus bradycardia (heart rate less than 50 bpm) or hypotension (systolic blood pressure less than 90 mm Hg) generally should not receive beta-blockers until these conditions have resolved. Patients with significant COPD who may have a component of reactive airway disease should be administered beta-blockers very cautiously; initially, low doses of a beta1-selective agent should be used. If there are concerns about possible intolerance to beta-blockers, initial selection should favor a short-acting beta1-specific drug such as metoprolol. Mild wheezing or a history of COPD mandates a short-acting cardioselective agent at a reduced dose (e.g., 2.5 mg metoprolol IV or 12.5 mg metoprolol orally or 25 mcg · kg^-1 · min^-1 esmolol IV as initial doses) rather than the complete avoidance of a beta-blocker.

In the absence of these concerns, several regimens may be used. For example, intravenous metoprolol may be given in 5-mg increments by slow intravenous administration (5 mg over 1 to 2 min), repeated every 5 min for a total initial dose of 15 mg. In patients who tolerate the total 15 mg IV dose, oral therapy should be initiated 15 min after the last intravenous dose at 25 to 50 mg every 6 h for 48 h. Thereafter, patients should receive a maintenance dose of 100 mg twice daily. Alternatively, intravenous propranolol is administered as an initial dose of 0.5 to 1.0 mg, followed in 1 to 2 h by 40 to 80 mg by mouth every 6 to 8 h. Intravenous esmolol is administered as a starting dose of 0.1 mg · kg^-1 · min^-1 with titration in increments of 0.05 mg · kg^-1 · min^-1 every 10 to 15 min as tolerated by the patient's blood pressure until the desired therapeutic response has been obtained, limiting symptoms develop, or a dosage of 0.3 mg · kg^-1 · min^-1 is reached. A loading dose of 0.5 mg per kg may be given by slow intravenous administration (2 to 5 min) for a more rapid onset of action. In patients suitable to receive a longer-acting agent, intravenous atenolol can be initiated with a 5-mg IV dose followed 5 min later by a second 5-mg IV dose and then 50 to 100 mg per day orally initiated 1 to 2 h after the intravenous dose. Monitoring during intravenous beta-blocker therapy should include frequent checks of heart rate and blood pressure and continuous ECG monitoring, as well as auscultation for rales and bronchospasm.

After the initial intravenous load, patients without limiting side effects may be converted to an oral regimen. The target resting heart rate is 50 to 60 bpm, unless a limiting side effect is reached. Selection of the oral agent should be based on the clinician's familiarity with the agent. Maintenance doses are given in Table 12.

Initial studies of beta-blocker benefits in ACS were small and uncontrolled. An overview of double-blind, randomized trials in patients with threatening or evolving MI suggests an approximately 13% reduction in the risk of progression to AMI ⁽¹⁴²⁾. These trials lack sufficient power to assess the effects of these drugs on mortality rates for UA. However, randomized trials with other CAD patients (AMI, recent MI, stable angina with daily life ischemia, and heart failure) have all shown reductions in mortality and/or morbidity rates. Thus, the rationale for beta-blocker use in all forms of CAD, including UA, is very compelling and in the absence of contraindications is sufficient to make beta-blockers a routine part of care, especially in patients who are to undergo cardiac or noncardiac surgery.

In conclusion, evidence for the beneficial effects of the use of beta-blockers in patients with UA is based on limited randomized trial data, along with pathophysiological considerations and extrapolation from experience with CAD patients who have other types of ischemic syndromes (stable angina, AMI, or heart failure). The recommendation for the use of intravenous beta-blockers in high-risk patients with evolving pain is based on the demonstrated benefit in AMI patients, as well as the hemodynamic objectives to reduce cardiac work and myocardial oxygen demand. The duration of benefit with long-term oral therapy is uncertain.

d. Calcium Antagonists
These agents reduce cell transmembrane inward calcium flux, which inhibits both myocardial and vascular smooth muscle contraction; some also slow AV conduction and depress sinus node impulse formation. Agents in this class vary in the degree to which they produce vasodilation, decreased myocardial contractility, AV block, and sinus node slowing. Nifedipine and amlodipine have the most peripheral arterial dilatory effect but little or no AV or sinus node effects, whereas verapamil and diltiazem have prominent AV and sinus node effects and some peripheral arterial dilatory effects as well. All 4 of these agents, as well as the newer agents, have coronary dilatory properties that appear to be similar. Although different members of this class of agents are structurally diverse and may have somewhat different mechanisms of action, no reliable data demonstrate the superiority of 1 agent (or groups of agents) over another in ACS, except for the risks posed by rapid-release, short-acting dihydropyridines (Table 13). Beneficial effects in ACS are believed to be due to variable combinations of decreased myocardial oxygen demand that relate to decreased afterload, contractility, and heart rate and improved myocardial flow that relates to coronary artery and arteriolar dilation ^(141,143). These agents also have theoretical beneficial effects on LV relaxation and arterial compliance. Major side effects include hypotension, worsening CHF, bradycardia, and AV block.

Calcium antagonists may be used to control ongoing or recurring ischemia-related symptoms in patients who are already receiving adequate doses of nitrates and beta-blockers, in patients who are unable to tolerate adequate doses of 1 or both of these agents, or in patients with variant angina (see Section VI. F). In addition, these drugs have been used for the management of hypertension in patients with recurrent UA ⁽¹⁴³⁾. Rapid-release, short-acting dihydropyridines (e.g., nifedipine) must be avoided in the absence of adequate concurrent beta-blockade in ACS because controlled trials suggest increased adverse outcomes ^(144-146). Verapamil and diltiazem should be avoided in patients with pulmonary edema or evidence of severe LV dysfunction ^(147,148). Amlodipine and felodipine, however, appear to be well tolerated by patients with chronic LV dysfunction ⁽¹⁴⁹⁾. The choice of an individual calcium antagonist is based primarily on the type of agent; the hemodynamic state of the patient; the risk of adverse effects on cardiac contractility, AV conduction, and sinus node function; and the physician's familiarity with the specific agent. Trials in patients with acute CAD suggest that verapamil and diltiazem are preferred if a calcium antagonist is needed ^(148,149).

There are several randomized trials that involve the use of calcium antagonists in ACS. Results generally confirm that these agents relieve or prevent symptoms and related ischemia to a degree similar to that of beta-blockers. The largest randomized trial is the Danish Study Group on Verapamil in Myocardial Infarction (DAVIT) ^(150,151), in which 3,447 patients with suspected ACS were administered intravenous verapamil (0.1 mg per kg) at admission and then 120 mg 3 times daily vs. placebo. After 1 week, verapamil was discontinued in the patients (n = 2,011) without confirmed MI (presumably many of these patients had UA). Although there was no definitive evidence to suggest benefit (or harm) in this cohort, trends favored a reduction in the outcome of death or nonfatal MI. In the Holland Interuniversity Nifedipine/metoprolol Trial (HINT), nifedipine and metoprolol were tested in a 2 × 2 factorial design in 515 patients ⁽¹⁴⁶⁾. Nifedipine alone increased the risk of MI or recurrent angina relative to placebo by 16%, metoprolol decreased it by 24%, and the combination of metoprolol and nifedipine reduced this outcome by 20%. None of these effects, however, were statistically significant because the study was stopped early because of concern for harm with the use of nifedipine alone. However, in patients already taking a beta-blocker, the addition of nifedipine appeared favorable because the event rate was reduced significantly (risk ratio [RR] 0.68) ⁽¹⁵²⁾. Several meta-analyses that combined all of the calcium antagonists used in UA trials suggested no overall effect ^(142,153). However, in light of the aforementioned differences between the rapid-release dihydropyridines and the heart rate-slowing agents diltiazem and verapamil, such analyses are not appropriate. When the data for verapamil are considered alone, a beneficial effect in patients with ACS is apparent ⁽¹⁵⁰⁾.

Similarly, in the Diltiazem Reinfarction Study (DRS), 576 patients were administered diltiazem or placebo 24 to 72 h after the onset of non-Q-wave MI ⁽¹⁴⁵⁾. Diltiazem was associated with a reduction in CK-MB level-confirmed reinfarction and refractory angina at 14 days without a significant increase in mortality rates. Retrospective analysis of the non-Q-wave MI subset of patients in the Multicenter Diltiazem Postinfarction Trial (MDPIT) suggested similar findings without evidence of harm ⁽¹⁵⁴⁾.

However, retrospective analyses of DAVIT and MDPIT suggested that the administration of verapamil and diltiazem to suspected AMI patients who have LV dysfunction (many of whom had UA/NSTEMI) may have an overall detrimental effect on mortality rates ^(145,147). Although this caution is useful for clinical practice, more recent data suggest that this issue should be readdressed. For example, in DAVIT-2, verapamil was associated with a significant reduction in diuretic use compared with placebo ⁽¹⁵⁵⁾, suggesting that it did not further impair LV function. Furthermore, recent prospective trials with verapamil administered to AMI patients with heart failure who were receiving an ACEI strongly suggest benefit ^(147,156). The Diltiazem as Adjunctive Therapy to Activase (DATA) trial also suggests that intravenous diltiazem in AMI patients may be safe; death, MI, or recurrent ischemia decreased by 14% at 35 days and death, MI, or refractory ischemia decreased by 23% at 6 months ⁽¹⁵⁷⁾. These pilot data were confirmed in 874 AMI patients without heart failure in whom long-acting diltiazem (300 mg per day) was administered 36 to 96 h after thrombolysis ⁽¹⁵⁸⁾ (W.E. Boden, oral presentation, American Heart Association Scientific Sessions, Dallas, Texas, November 1998).

In conclusion, definitive evidence for benefit with all calcium antagonists in UA is predominantly limited to symptom control. For dihydropyridines, available randomized trial data are not consistent with a beneficial effect on mortality or recurrent infarction rates but in fact provide strong evidence for an increase in these serious events when they are administered early as a rapid-release, short-acting preparation without a beta-blocker. Thus, these guidelines recommend reservation of the dihydropyridine calcium antagonists as second or third choices after the initiation of nitrates and beta-blockers. For the heart rate-slowing drugs (verapamil and diltiazem), there is no controlled trial evidence for harm when they are administered early to patients with acute ischemic syndromes, and strong trends suggest a beneficial effect. Therefore, when beta-blockers cannot be used, heart rate-slowing calcium antagonists offer an alternative. When required for refractory symptom control, these agents can be used early during the hospital phase, even in patients with mild LV dysfunction, although the combination of a beta-blocker and calcium antagonist may act in synergy to depress LV function. The risks and benefits in UA of amlodipine and other newer agents relative to the older agents in this class reviewed here remain undefined.

e. Other
ACEIs have been shown to reduce mortality rates in patients with AMI or who recently had an MI and have LV systolic dysfunction ^{(159-161,161a)}, in diabetic patients with LV dysfunction ⁽¹⁶²⁾, and in a broad spectrum of patients with high-risk chronic CAD, including patients with normal LV function ⁽¹⁶³⁾. Accordingly, ACEIs should be used in such patients as well as in those with hypertension that is not controlled with beta-blockers and nitrates.

Other less extensively studied techniques for the relief of ischemia, such as spinal cord stimulation ⁽¹⁶⁴⁾ and prolonged external counterpulsation ^(165,166), are under evaluation. Most experience has been gathered with spinal cord stimulation in "intractable angina" ⁽¹⁶⁷⁾, in which anginal relief has been described.

The KATP channel openers have hemodynamic and cardioprotective effects that could be useful in UA/NSTEMI. Nicorandil is such an agent that is approved in a number of countries but not yet in the United States. In a pilot double-blind, placebo-controlled study of 245 patients with UA, the addition of this drug to conventional treatment significantly reduced the number of episodes of transient myocardial ischemia (mostly silent) and of ventricular and supraventricular tachycardia ⁽¹⁶⁸⁾. Further evaluation of this class of agents is under way.

B. Antiplatelet and Anticoagulation Therapy

Recommendations for Antiplatelet and Anticoagulation Therapy

Class I

1. Antiplatelet therapy should be initiated promptly. ASA should be administered as soon as possible after presentation and continued indefinitely. (Level of Evidence: A)
2. Clopidogrel should be administered to hospitalized patients who are unable to take ASA because of hypersensitivity or major gastrointestinal intolerance. (Level of Evidence: A)
3. In hospitalized patients in whom an early noninterventional approach is planned, clopidogrel should be added to ASA as soon as possible on admission and administered for at least 1 month (Level of Evidence: A) and for up to 9 months (Level of Evidence: B)
4. In patients for whom a PCI is planned, clopidogrel should be started and continued for at least 1 month (Level of Evidence: A) and up to 9 months in patients who are not at high risk for bleeding (Level of Evidence: B)
5. In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5 to 7 days. (Level of Evidence: B)
6. Anticoagulation with subcutaneous LMWH or intravenous unfractionated heparin (UFH) should be added to antiplatelet therapy with ASA and/or clopidogrel. (Level of Evidence: A)
7. A platelet GP IIb/IIIa antagonist should be administered, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: A)

Class IIa

1. Eptifibatide or tirofiban should be administered, in addition to ASA and LMWH or UFH, to patients with continuing ischemia, an elevated troponin or with other high-risk features in whom an invasive management strategy is not planned. (Level of Evidence: A)
2. Enoxaparin is preferable to UFH as an anticoagulant in patients with UA/NSTEMI, unless CABG is planned within 24 h. (Level of Evidence: A)
3. A platelet GP IIb/IIIa antagonist should be administered to patients already receiving heparin, ASA, and clopidogrel in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI. (Level of Evidence: B)

Class IIb

Eptifibatide or tirofiban, in addition to ASA and LMWH or UFH, to patients without continuing ischemia who have no other high-risk features and in whom PCI is not planned. (Level of Evidence: A)

Class III

1. Intravenous fibrinolytic therapy in patients without acute ST-segment elevation, a true posterior MI, or a presumed new left bundle-branch block (LBBB). (Level of Evidence: A)
2. Abciximab administration in patients in whom PCI is not planned. (Level of Evidence: A)

Antithrombotic therapy is essential to modify the disease process and its progression to death, MI, or recurrent MI. A combination of ASA, UFH, and a platelet GP IIb/IIIa receptor antagonist represents the most effective therapy. The intensity of treatment is tailored to individual risk, and triple antithrombotic treatment is used in patients with continuing ischemia or with other high-risk features and in patients oriented to an early invasive strategy (Table 14). Table 15 shows the recommended doses of the various agents. An LMWH can be advantageously substituted for UFH, although experience with the former in PCI, in patients referred for urgent CABG, and in combination with a GP IIb/IIIa antagonist and with a thrombolytic agent is limited. In the ESSENCE ⁽¹⁶⁹⁾ and TIMI 11B trials ^(170,171) in UA and NSTEMI, enoxaparin was stopped 6 to 12 h before a planned percutaneous procedure or surgery and UFH was substituted. Trials are now under way to test the safety and efficacy of enoxaparin in patients undergoing PCI and of enoxaparin and dalteparin combined with a GP IIb/IIIa antagonist and with a lytic agent. A pilot double-blind, randomized study of 55 patients compared the combination of tirofiban and enoxaparin with the combination of tirofiban and UFH. The results suggested more reproducible inhibition of platelet aggregation with enoxaparin and less prolongation in bleeding time. There was an excess of minor bleeding with enoxaparin but not of major bleeding ⁽¹⁷²⁾. Furthermore, there may be problems in rapid reversal of the anticoagulation when required, such as before CABG.

1. Antiplatelet Therapy (Aspirin, Ticlopidine, Clopidogrel)
a. Aspirin
Some of the strongest evidence available about the long-term prognostic effects of therapy in patients with coronary disease pertains to ASA ⁽¹⁷³⁾. By irreversibly inhibiting cyclooxygenase-1 within platelets, ASA prevents the formation of thromboxane A2, thereby diminishing platelet aggregation promoted by this pathway but not by others. This platelet inhibition is the plausible mechanism for clinical benefit of ASA because it is fully present with low doses of ASA and because platelets represent one of the principal participants in thrombus formation after plaque disruption. Alternative or additional mechanisms of action for ASA are possible, such as an anti-inflammatory effect ⁽¹⁷⁴⁾, but they are unlikely at the low doses of ASA that are effective in UA/NSTEMI.

Among all clinical investigations with ASA, trials in UA/NSTEMI have most consistently documented a striking benefit of the drug independent of the differences in study design, such as time of entry after the acute phase, duration of follow-up, and doses used ^(175-178) (Figure 8).

No trial has directly compared the efficacy of different doses of ASA in patients who present with UA/NSTEMI. However, trials in secondary prevention of stroke, MI, death, and graft occlusion have not shown an added benefit for ASA doses of greater than 80 and 160 mg per d but have shown a higher risk of bleeding. An overview of trials with different doses of ASA in long-term treatment of patients with CAD suggests similar efficacy for daily doses ranging from 75 to 324 mg ⁽¹⁷³⁾. A dose of 160 mg per d was used in the Second International Study of Infarct Survival (ISIS-2) trial, which definitively established the efficacy of ASA in suspected MI ⁽¹⁸⁵⁾. It therefore appears reasonable to initiate ASA treatment in patients with UA/NSTEMI at a dose of 160 mg, as used in the ISIS-2 trial, or 325 mg. In patients who present with suspected ACS who are not already receiving ASA, the first dose may be chewed to rapidly establish a high blood level. Subsequent doses may be swallowed. Thereafter, daily doses of 75 to 325 mg are prescribed.

The prompt action of ASA and its ability to reduce mortality rates in patients with suspected AMI enrolled in the ISIS-2 trial led to the recommendation that ASA be initiated immediately in the ED as soon as the diagnosis of ACS is made or suspected. In patients who are already receiving ASA, it should be continued. The protective effect of ASA has been sustained for at least 1 to 2 years in clinical trials in UA. Longer-term follow-up data in this population are lacking. Given the relatively short-term prognostic impact of UA/NSTEMI in patients with coronary disease, long-term efficacy can be extrapolated from other studies of ASA therapy in CAD. Studies in patients with prior MI, stroke, or transient ischemic attack have shown statistically significant benefit during the first 2 years and some additional but not statistically significant benefit during the third year ⁽¹⁷³⁾. In the absence of large comparison trials of different durations of antiplatelet treatment in patients with cardiovascular disease or in primary prevention, it seems prudent to continue ASA indefinitely unless side effects are present ^(5,26,173). Thus, patients should be informed of the evidence that supports the use of ASA in UA/NSTEMI and CAD in general and instructed to continue the drug indefinitely, unless a contraindication develops.

Contraindications to ASA include intolerance and allergy (primarily manifested as asthma), active bleeding, hemophilia, active retinal bleeding, severe untreated hypertension, an active peptic ulcer, or another serious source of gastrointestinal or genitourinary bleeding. Gastrointestinal side effects such as dyspepsia and nausea are infrequent with the low doses. Acute gout due to impaired urate excretion is rarely precipitated. Primary prevention trials have reported a small excess in intracranial bleeding, which is offset in secondary prevention trials by the prevention of ischemic stroke. It has been proposed that there is a negative interaction between ACEIs and ASA with a reduction in the vasodilatory effects of ACEIs, presumably because ASA inhibits ACEI-induced prostaglandin synthesis. This interaction does not appear to interfere with the clinical benefits of therapy with either agent ⁽¹⁸⁶⁾. Therefore, unless there are specific contraindications, ASA should be administered to all patients with UA/NSTEMI.

b. Adenosine Diphosphate Receptor Antagonists and Other Antiplatelet Agents
Two thienopyridines-ticlopidine and clopidogrel-are adenosine diphosphate (ADP) antagonists that are currently approved for antiplatelet therapy ⁽¹⁸⁷⁾. The platelet effects of ticlopidine and clopidogrel are irreversible but take several days to become completely manifest. Because the mechanisms of the antiplatelet effects of ASA and ADP antagonists differ, a potential exists for additive benefit with the combination.

Ticlopidine has been used successfully for the secondary prevention of stroke and MI and for the prevention of stent closure and graft occlusion. In an open-label trial ⁽¹⁸⁸⁾, 652 patients with UA were randomized to receive 250 mg of ticlopidine twice a day or standard therapy without ASA. At 6-month follow-up, ticlopidine reduced the rate of fatal and nonfatal MI by 46% (13.6% vs. 7.3%, p = 0.009). The benefit of ticlopidine in the study developed after only 2 weeks of treatment, which is consistent with the delay of the drug to achieve full effect.

The adverse effects of ticlopidine limit its usefulness: gastrointestinal problems (diarrhea, abdominal pain, nausea, vomiting), neutropenia in approximately 2.4% of patients, severe neutropenia in 0.8% of patients, and, rarely, thrombotic thrombocytopenia purpura (TTP) ⁽¹⁸⁹⁾. Neutropenia usually resolves within 1 to 3 weeks of discontinuation of therapy but very rarely may be fatal. TTP, which also is a very uncommon life-threatening complication, requires immediate plasma exchange. Monitoring of ticlopidine therapy requires a complete blood count that includes a differential count every 2 weeks for the first 3 months of therapy.

Most clinical experience with clopidogrel is derived from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial ⁽¹⁹⁰⁾. A total of 19,185 patients were randomized to receive 325 mg per day ASA or 75 mg per day clopidogrel. Entry criteria consisted of atherosclerotic vascular disease manifested as recent ischemic stroke, recent MI, or symptomatic peripheral arterial disease. Follow-up extended for 1 to 3 years. The RR of ischemic stroke, MI, or vascular death was reduced by 8.7% in favor of clopidogrel from 5.83% to 5.32% (p = 0.043). There was a slightly increased, but minimal, incidence of rash and diarrhea with clopidogrel treatment and slightly more bleeding with ASA. There was no excess neutropenia with clopidogrel, which contrasts with ticlopidine. The results provide evidence that clopidogrel is at least as effective as ASA and may be modestly more effective. In a recent report, 11 severe cases of TTP were described as occurring within 14 days after the initiation of clopidogrel; plasma exchange was required in 10 of the patients, and 1 patient died ⁽¹⁹¹⁾. These cases occurred among more than 3 million patients treated with clopidogrel.

Ticlopidine or clopidogrel is reasonable antiplatelet therapy for secondary prevention with an efficacy at least similar to that of ASA. These drugs are indicated in patients with UA/NSTEMI who are unable to tolerate ASA due to either hypersensitivity or major gastrointestinal contraindications, principally recent significant bleeding from a peptic ulcer or gastritis. Care must be taken during the acute phase with these drugs because of the delays required to achieve a full antiplatelet effect. Clopidogrel is preferred to ticlopidine because it more rapidly inhibits platelets and appears to have a more favorable safety profile. Experience is being acquired with this drug in acute situations with a loading dose (300 mg) to achieve more rapid platelet inhibition. Initial treatment with heparin (UFH or LMWH) and probably with a GP IIb/IIIa antagonist is especially important in patients with UA/NSTEMI who are treated with 1 of the thienopyridines because of their delayed onset of antiplatelet activity compared with ASA.

Two randomized trials were recently completed in which clopidogrel was compared with ticlopidine. In 1 study, 700 patients who successfully received a stent were randomized to receive 500 mg of ticlopidine or 75 mg of clopidogrel, in addition to 100 mg of ASA, for 4 weeks ⁽¹⁹²⁾. Cardiac death, urgent target vessel revascularization, angiographically documented thrombotic stent occlusion, or nonfatal MI within 30 days occurred in 3.1% of patients who received clopidogrel and 1.7% of patients who received ticlopidine (p = 0.24), and noncardiac death, stroke, severe peripheral vascular hemorrhagic events, or any adverse event that resulted in the discontinuation of the study medication occurred in 4.5% and 9.6% of patients, respectively (p = 0.01). The CLopidogrel ASpirin Stent International Cooperative Study (CLASSICS) (P. Urban, A.H. Gershlick, H.-J. Rupprecht, M.E. Bertrands, oral presentation, American Heart Association Scientific Sessions, Atlanta, Ga, November 1999) was conducted in 1,020 patients. A loading dose of 300 mg of clopidogrel followed by 75 mg per day was compared to a daily dose of 75 mg without a loading dose and with a loading dose of 150 mg of ticlopidine followed by 150 mg twice a day (patients in each of the 3 arms also received ASA). The first dose was administered 1 to 6 h after stent implantation; the treatment duration was 28 days. The trial showed better tolerance to clopidogrel with or without a loading dose than to ticlopidine. Stent thrombosis or major complications occurred at the same frequency in the 3 groups.

The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial randomized 12,562 patients with UA and NSTEMI presenting within 24 h to placebo or clopidogrel (loading dose of 300 mg followed by 75 mg daily) and followed them for 3 to 12 months. All patients received aspirin. Cardiovascular death, MI, or stroke occurred in 11.5% of patients assigned to placebo and 9.3% assigned to clopidogrel (RR = 0.80, p less than 0.001). In addition, clopidogrel was associated with significant reductions in the rate of inhospital severe ischemia and revascularization, as well as the need for thrombolytic therapy or intravenous GP IIb/IIIa receptor antagonists. These results were observed across a wide variety of subgroups. A reduction in recurrent ischemia was noted within the first few hours after randomization.

There was an excess of major bleeding (2.7% in the placebo group vs. 3.7% in the clopidogrel group, p = 0.003) as well as of minor but not of life-threatening bleeding. The risk of bleeding was increased in patients undergoing CABG surgery within the first 5 days of stopping clopidogrel. CURE was conducted at centers in which there was no routine policy of early invasive procedures; revascularization was performed during the initial admission in only 23% of the patients. Although the addition of a platelet GP IIb/IIIa inhibitor in patients receiving ASA, clopidogrel, and heparin in CURE was well tolerated, fewer than 10% of patients received this combination. Therefore, additional information on the safety of the addition of heparin (LMWH or UFH) and a GP IIb/IIIa inhibitor in patients already receiving ASA and clopidogrel should be obtained. Also, it is not yet clear whether clopidogrel improved the outcome in patients who received GP IIb/IIIa antagonists.

This trial provides strong evidence for the addition of clopidogrel to ASA on admission in the management of patients with UA and NSTEMI, in whom a noninterventional approach is intended-an especially useful approach in hospitals that do not have a routine policy of early invasive procedures. The optimal duration of therapy with clopidogrel has not been determined, but the favorable results in CURE were observed over a period averaging 9 months.

In the PCI-CURE study, 2,658 patients undergoing PCI had been randomly assigned double-blind treatment with clopidogrel (n = 1,313) or placebo (n = 1,345). Patients were pretreated with aspirin and the study drug for a median of 10 days. After PCI, most patients received open-label thienopyridine for about 4 weeks, after which the study drug was restarted for a mean of 8 months. Fifty-nine patients (4.5%) in the clopidogrel group had the primary end point-a composite of cardiovascular death, MI, or urgent target-vessel revascularization-within 30 days of PCI compared with 86 (6.4%) in the placebo group (relative risk 0.70 [95% Confidence Interval {CI} 0.50-0.97], p = 0.03). Overall (including events before and after PCI), there was a 31% reduction in cardiovascular death or MI (p = 0.002). Thus, in patients with UA and NSTEMI receiving ASA and undergoing PCI, a strategy of clopidogrel pretreatment followed by at least 1 month and probably longer-term therapy is beneficial in reducing major cardiovascular events compared with placebo ⁽⁵²²⁾. Therefore, clopidogrel should be used routinely in patients who undergo PCI.

There now appears to be an important role for clopidogrel in patients with UA/NSTEMI, both those who are managed conservatively as well as those who undergo PCI, especially stenting. However, it is not entirely clear how long therapy should be maintained. Since clopidogrel, when added to ASA, increases the risk of bleeding during major surgery in patients who are scheduled for elective CABG, clopidogrel should be withheld for at least 5 days ⁽⁵²¹⁾, and preferably for 7 days before surgery ⁽⁵²³⁾. In many hospitals in which patients with UA/NSTEMI undergo diagnostic catheterization within 24 to 36 h of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. A loading dose of clopidogrel can be given to a patient on the catheterization table if a PCI is to be carried out immediately. If PCI is not carried out, the clopidogrel can be begun after the catheterization.

Sulfinpyrazone, dipyridamole, prostacyclin, and prostacyclin analogs have not been associated with benefit in UA or NSTEMI and are not recommended. The thromboxane synthase blockers and thromboxane A2 receptor antagonists have been evaluated in ACS but have not shown any advantage over ASA. A number of other antiplatelet drugs are currently available, and still others are under active investigation. Oral GP IIb/IIIa receptor blockers were tested in 1 PCI trial and 3 UA/NSTEMI trials; the 4 trials failed to document a benefit and 2 showed an excess mortality rate ^{(193,193a,193b)}.

Clopidogrel is the preferred thienopyridine because of its more rapid onset of action, especially after a loading dose ^(524,525) and better safety profile than ticlopidine ⁽⁵²⁶⁾.

2. Anticoagulants
Anticoagulants available for parenteral use include UFH, various LMWHs, and hirudin, and for oral use, the antivitamin K drugs are available. Synthetic pentasaccharides and synthetic direct thrombin inhibitors (argatroban, bivaluridine) as well as oral direct and indirect thrombin inhibitors are under clinical investigation. Hirudin is approved as an anticoagulant in patients with heparin-induced thrombocytopenia and for the prophylaxis of deep vein thrombosis after hip replacement.

Heparin exerts its anticoagulant effect by accelerating the action of circulating antithrombin, a proteolytic enzyme that inactivates factor IIa (thrombin), factor IXa, and factor Xa. It prevents thrombus propagation but does not lyse existing thrombi ⁽¹⁹⁴⁾. UFH is a heterogeneous mixture of chains of molecular weights that range from 5,000 to 30,000 and have varying effects on anticoagulant activity. UFH binds to a number of plasma proteins, blood cells, and endothelial cells. The LMWHs are obtained through chemical or enzymatic depolymerization of the polysaccharide chains of heparin to provide chains with different molecular weight distributions. About 25% to 50% of the pentasaccharide-containing chains of LMWH preparations contain greater than 18 saccharide units, and these are able to inactivate both thrombin and factor Xa. However, LMWH chains that are less than 18 saccharide units retain their ability to inactivate factor Xa but not thrombin. Therefore, LMWHs are relatively more potent in the catalyzation of the inhibition of factor Xa by antithrombin than in the inactivation of thrombin. Distinct advantages of LMWH over UFH include decreased binding to plasma proteins and endothelial cells and dose-independent clearance with a longer half-life that results in more predictable and sustained anticoagulation with once- or twice-a-day subcutaneous administration. A major advantage of LMWHs is that they do not usually require laboratory monitoring of activity. The pharmacodynamic and pharmacokinetic profiles of the different commercial preparations of LMWHs vary, with their mean molecular weights ranging from 4,200 to 6,000. Accordingly, their ratios of anti-Xa factor to anti-IIa factor vary, ranging from 1.9 to 3.8 ⁽¹⁹⁵⁾.

By contrast, the direct thrombin inhibitors very specifically block thrombin effects without the need for a cofactor such as antithrombin. Hirudin binds directly to the anion binding site and the catalytic sites of thrombin to produce potent and predictable anticoagulation ⁽¹⁹⁶⁾. Several large trials (see later) that compare hirudin with UFH in UA/NSTEMI have demonstrated a modest short-term reduction in the composite end point of death or nonfatal MI with a modest increase in the risk of bleeding.

Bivalurudin (Hirulog) is a synthetic analog of hirudin that binds reversibly to thrombin. It has been compared with UFH in several small trials in UA/NSTEMI and in PCI with some evidence of a reduction in death or MI and less bleeding than with UFH ^(197-199).

a. Unfractionated Heparin
Seven randomized, placebo-controlled trials with UFH have been reported ^(200-205). A placebo-controlled study performed by Theroux et al. ⁽¹⁷⁷⁾ between 1986 and 1988 tested treatments that consisted of ASA and a 5,000-U IV bolus of UFH followed by 1,000 U per h in a 2 × 2 factorial design. UFH reduced the risk of MI by 89% and the risk of recurrent refractory angina by 63%. An extension of this study compared ASA and UFH in UA patients. MI (fatal or nonfatal) occurred in 3.7% of patients who received ASA and 0.8% of patients who received UFH (p = 0.035) ⁽²⁰²⁾.

The Research Group in Instability in Coronary Artery Disease (RISC) trial was a double-blind, placebo-controlled trial with a 2 × 2 factorial design that was conducted in men with UA or NSTEMI ⁽¹⁷⁸⁾. ASA significantly reduced the risk of death or MI. UFH alone had no benefit, although the group treated with the combination of ASA and UFH had the lowest number of events during the initial 5 days. Neri-Seneri et al. ⁽²⁰³⁾ suggested that symptomatic and silent episodes of ischemia in UA could be prevented by an infusion of UFH but not by bolus injections or by ASA. Taken together, these trials indicate that the early administration of UFH is associated with a reduction in the incidence of AMI and ischemia in patients with UA/NSTEMI.

The results of the studies that have compared the combination of ASA and heparin with ASA alone are shown in Figure 8. In the trials that used UFH, the reduction in the rate of death or MI during the first week was 54% (p = 0.016), and in the trials that used either UFH or LMWH, the reduction was 63%. Two published meta-analyses have included different studies. In 1 meta-analysis, which involved 3 randomized trials and an early end point (less than 5 days) ⁽¹⁷⁹⁾, the risk of death or MI with the combination of ASA and heparin was reduced by 56% (p = 0.03). In the second meta-analysis, which involved 6 trials and end points that ranged from 2 to 12 weeks, the RR was reduced by 33% (p = 0.06) ⁽²⁰⁶⁾. Most of the benefits of the various anticoagulants are short term, however, and not maintained on a long-term basis. Reactivation of the disease process after the discontinuation of anticoagulants may contribute to this loss of early gain that has been described with UFH ⁽²⁰⁷⁾, dalteparin ⁽¹⁸¹⁾, and hirudin ^(208,209). The combination of UFH and ASA appears to mitigate this reactivation in part ^(207,210), although there is hematologic evidence of increased thrombin activity after the cessation of intravenous UFH even in the presence of ASA ⁽²¹¹⁾. Uncontrolled observations suggested a reduction in the "heparin rebound" by switching from intravenous to subcutaneous UFH for several days before the drug is stopped.

UFH has important pharmacokinetic limitations that are related to its nonspecific binding to proteins and cells. These pharmacokinetic limitations of UFH translate into poor bioavailability, especially at low doses, and marked variability in anticoagulant response among patients ⁽²¹²⁾. As a consequence of these pharmacokinetic limitations, the anticoagulant effect of heparin requires monitoring with the activated partial thromboplastin time (aPTT), a test that is sensitive to the inhibitory effects of UFH on thrombin (factor IIa), factor Xa, and factor IXa. Many clinicians have traditionally prescribed a fixed initial dose of UFH (e.g., 5,000-U bolus, 1,000 U per h initial infusion); clinical trials have indicated that a weight-adjusted dosing regimen could provide more predictable anticoagulation than the fixed-dose regimen ^(213-215). The weight-adjusted regimen is recommended with an initial bolus of 60 to 70 U per kg (maximum 5,000 U) and an initial infusion of 12 to 15 U · kg^-1 · h^-1·(maximum 1,000 U per h). The therapeutic range of the various nomograms differs due to variation in the laboratory methods used to determine aPTT. The American College of Chest Physicians consensus conference ⁽²¹²⁾ has therefore recommended dosage adjustments of the nomograms to correspond to a therapeutic range equivalent to heparin levels of 0.3 to 0.7 U per mL by anti-factor Xa determinations, which correlates with aPTT values between 60 and 80 s. In addition to body weight, other clinical factors that affect the response to UFH include age, which is associated with higher aPTT values, and smoking history and diabetes mellitus, which are associated with lower aPTT values ^(212,216).

Thus, even though weight-based UFH dosing regimens are used, the aPTT should be monitored for adjustment of UFH dosing. Because of variation among hospitals in the control aPTT values, nomograms should be established at each institution that are designed to achieve aPTT values in the target range (e.g., for a control aPTT of 30 s, the target range [1.5 to 2.5 times control] would be 45 to 75 s). Measurements should be made 6 h after any dosage change and used to adjust UFH infusion until the aPTT exhibits a therapeutic level. When 2 consecutive aPTT values are therapeutic, the measurements may be made every 24 h and, if necessary, dose adjustment carried out. In addition, a significant change in the patient's clinical condition (e.g., recurrent ischemia, bleeding, hypotension) should prompt an immediate aPTT determination, followed by dose adjustment, if necessary.

Serial hemoglobin/hematocrit and platelet measurements are recommended at least daily during UFH therapy. In addition, any clinically significant bleeding, recurrent symptoms, or hemodynamic instability should prompt their immediate determination. Serial platelet counts are necessary to monitor for heparin-induced thrombocytopenia. Mild thrombocytopenia may occur in 10% to 20% of patients who are receiving heparin, whereas severe thrombocytopenia (platelet count less than 100,000) occurs in 1% to 2% of patients and typically appears after 4 to 14 days of therapy. A rare but dangerous complication (less than 0.2% incidence) is autoimmune UFH-induced thrombocytopenia with thrombosis ⁽²¹⁷⁾. A high clinical suspicion mandates the immediate cessation of all heparin therapy (including that used to flush intravenous lines).

Most of the trials that evaluate the use of UFH in UA/NSTEMI have continued therapy for 2 to 5 days. The optimal duration of therapy remains undefined.

b. Low-Molecular-Weight Heparin
In a pilot open-label study, 219 patients with UA were randomized to receive ASA (200 mg per d), ASA plus UFH, or ASA plus nadroparin, an LMWH. The combination of ASA and LMWH significantly reduced the total ischemic event rate, the rate of recurrent angina, and the number of patients requiring interventional procedures ⁽¹⁸⁰⁾.

The FRISC study ⁽¹⁸¹⁾ randomized 1,506 patients with UA or non-Q-wave MI to receive subcutaneous administration of the LMWH dalteparin (120 IU per kg twice daily) or placebo for 6 days and then once a day for the next 35 to 45 days. Dalteparin was associated with a 63% risk reduction in death or MI during the first 6 days (4.8% vs. 1.8%, p = 0.001), matching the favorable experience observed with UFH. Although an excess of events was observed after the dose reduction to once daily after 6 days, a significant decrease was observed at 40 days with dalteparin in the composite outcome of death, MI, or revascularization (23.7% vs. 18.0%, p = 0.005), and a trend was noted in a reduction in rates of death or MI (10.7% vs. 8.0%, p = 0.07).

Because the level of anticoagulant activity cannot be easily measured in patients receiving LMWH (e.g., aPTT or activated clotting time [ACT]), interventional cardiologists have expressed concern about the substitution of LMWH for UFH in patients scheduled for catheterization with possible PCI. However, Collett et al. ⁽⁵²⁷⁾ showed in a study involving 293 patients with UA/NSTEMI who received the usual dose of enoxaparin that PCI can be performed safely.

In the National Investigators Collaborating on Enoxaparin Trial (NICE-1), an observational study, intravenous enoxaparin (1.0 mg per kg) was used in 828 patients undergoing elective PCI ⁽⁵²⁸⁾ without an intravenous GP IIb/IIIa inhibitor. The rate of bleeding (1.1% for major bleeding and 6.2% for minor bleeding in 30 days) was comparable to historical controls given UFH.

An alternative approach is to use LMWH during the period of initial stabilization. The dose can be withheld on the morning of the procedure, and if an intervention is required and more than 8 hours has elapsed since the last dose of LMWH, UFH can be used for PCI according to usual practice patterns. Because the anticoagulant effect of UFH can be more readily reversed than that of LMWH, UFH is preferred in patients likely to undergo CABG within 24 h.

c. LMWH Versus UFH
Four large randomized trials have directly compared an LMWH with UFH (Figure 9). In the FRagmin In unstable Coronary artery disease (FRIC) study, 1482 patients with UA/NSTEMI received open-label dalteparin (120 IU per kg subcutaneously twice a day) or UFH for 6 days ⁽²¹⁸⁾. At day 6 and until day 45, patients were randomized a second time to double-blind administration of dalteparin (120 IU per kg once a day) or placebo. During the first part of the study, the risk of death, MI, or recurrent angina was nonsignificantly increased with dalteparin (9.3% vs. 7.65%, p = 0.33), and the risk of death or MI was unaffected (3.9% vs. 3.6%, p = 0.8); death also tended to occur more frequently with dalteparin (1.5% vs. 0.4% with UFH, p = 0.057). Between days 6 and 45, the rates of death, MI, and recurrence of angina were comparable between the active treatment and placebo groups.

The ESSENCE trial ⁽¹⁶⁹⁾ compared enoxaparin (1 mg per kg twice daily subcutaneous administration) with standard UFH (5,000 U bolus), followed by an infusion titrated to an aPTT of 55 to 86 s, administered for 48 h to 8 days (median duration in both groups of 2.6 days) ⁽¹⁶⁹⁾. With UFH, only 46% of patients reached the target aPTT within 12 to 24 h. The composite outcome of death, MI, or recurrent angina was reduced by 16.2% at 14 days with enoxaparin (19.8% UFH vs. 16.6% enoxaparin, p = 0.019) and by 19% at 30 days (23.3% vs. 19.8%, p = 0.017). The rates of death were unaffected, whereas there were trends to reductions in the rates of death and MI by 29% (p = 0.06) at 14 days and by 26% (p = 0.08) at 30 days.

The TIMI 11B trial randomized 3,910 patients with UA/NSTEMI to enoxaparin (30 mg IV initial bolus immediately followed by subcutaneous injections of 1 mg per kg every 12 h) or UFH (70 U per kg bolus followed by an infusion of 15 U · kg^-1 · h^-1 titrated to a target aPTT 1.5 to 2.5 times control) ⁽¹⁷⁰⁾. The acute phase therapy was followed by an outpatient phase, during which enoxaparin or placebo for patients who were initially randomized to UFH was administered in a double-blind manner twice a day. Enoxaparin was administered for a median of 4.6 days, and UFH was administered for a median of 3.0 days. The composite end point of death, MI, or need for an urgent revascularization (defined as an episode of recurrent angina prompting the performance of coronary revascularization during the index hospitalization or after discharge leading to rehospitalization and coronary revascularization) was reduced at 8 days from 14.5% to 12.4% (p = 0.048) and at 43 days from 19.6% to 17.3% (p = 0.048). The rates of death or MI were reduced from 6.9% to 5.7% (p = 0.114) at 14 days and from 8.9% to 7.9% (p = 0.276) at 43 days. No incremental benefit was observed with outpatient treatment, whereas the risk of major bleeding was significantly greater during the outpatient treatment. The risk of minor bleeding was also increased both in and out of hospital with enoxaparin.

The FRAXiparine in Ischaemic Syndrome (FRAXIS) trial had 3 parallel arms and compared the LMWH nadroparin administered for 6 or 14 days with control treatment with UFH ⁽²¹⁹⁾. Three thousand four hundred sixty-eight patients with UA or NSTEMI were enrolled. The composite outcome of death, MI, or refractory angina occurred at 14 days in 18.1% of patients in the UFH group, 17.8% of patients treated with nadroparin for 6 days, and 20.0% of patients treated with nadroparin for 14 days; the values at 3 months were 22.2%, 22.3%, and 26.2% of patients, respectively (p less than 0.03 for the comparison of 14-day nadroparin therapy with UFH therapy). Trends to more frequent death and to more frequent death or MI were observed at all time points in nadroparin-treated patients.

Thus, 2 trials with enoxaparin have shown a moderate benefit over UFH, and 2 trials (1 with dalteparin and 1 with nadroparin) showed neutral or unfavorable trends. Whether the heterogeneous results are explained by different populations, study designs, various heparin dose regimens, properties of the various LMWHs (more specifically different molecular weights and anti-factor Xa/anti-factor IIa ratios), or other unrecognized influences is a matter of speculation. A meta-analysis of the 2 trials with enoxaparin that involved a total of 7,081 patients showed a statistically significant reduction of approximately 20% in the rate of death, MI, or urgent revascularization at 2, 8, 14, and 43 days and in the rate of death or MI at 8, 14, and 43 days. At 8, 14, and 43 days, there was a trend toward a reduction in death as well ⁽¹⁷¹⁾.

Although it is tempting to compare the relative treatment effects of the different LMWH compounds in Figure 9, the limitations of such indirect comparisons must be recognized. The only reliable method of comparing 2 treatments is through a direct comparison in a well-designed clinical trial or series of trials. The comparison of different therapies (e.g., different LMWHs) with a common therapy (e.g., UFH) in different trials does not allow a conclusion to be made about the relative effectiveness of the different LMWHs because of the variability in both control group and experimental group event rates due to protocol differences, differences in concomitant therapies due to geographical and time variability, and the play of chance. Similar considerations apply to comparisons among platelet GP IIb/IIIa inhibitors.

However, in the Enoxaparin Versus Tinzaparin (EVET) trial, 2 LMWHs, enoxaparin and tinzaparin, administered for 7 days were compared in 438 patients with UA/NSTEMI. A preliminary report stated that both the recurrence of UA and the need for revascularization were significantly lower in the enoxaparin group ⁽⁵²⁹⁾. The advantages of LMWH preparations are the ease of subcutaneous administration and the absence of a need for monitoring. Furthermore, the LMWHs stimulate platelets less than UFH ⁽²²⁰⁾ and are less frequently associated with heparin-induced thrombocytopenia ⁽²²¹⁾. They are associated with more frequent minor, but not major, bleeding. In the ESSENCE trial, minor bleeding occurred in 11.9% of enoxaparin patients and 7.2% of UFH patients (p less than 0.001), and major bleeding occurred in 6.5% and 7.0%, respectively. In TIMI 11B, the rates of minor bleeding in hospital were 9.1% and 2.5%, respectively (p less than 0.001), and the rates of major bleeding were 1.5% and 1.0% (p = 0.143). In the FRISC study, major bleeding occurred in 0.8% of patients with dalteparin and in 0.5% of patients with placebo, and minor bleeding occurred in 8.2% (61 of 746 patients) and 0.3% (2 of 760 patients) of patients, respectively. The anticoagulation provided with LMWH is less effectively reversed with protamine than it is with UFH. In addition, LMWH administered during PCI does not permit monitoring of the ACT to titrate the level of anticoagulation. In the ESSENCE and TIMI 11B trials, special rules were set to discontinue enoxaparin before PCI and CABG. UFH was administered during PCI to achieve ACT values of greater than 350 s. An economic analysis of the ESSENCE trial suggested cost savings with enoxaparin ⁽²²²⁾. For patients who are receiving subcutaneous LMWH and in whom CABG is planned, it is recommended that LMWH be discontinued and UFH be used during the operation. Additional experience with regard to the safety and efficacy of the concomitant administration of LMWHs with GP IIb/IIIa antagonists and thrombolytic agents is currently being acquired.

The FRISC, FRIC, TIMI 11B, and Fast Revascularization During Instability in Coronary Artery Disease (FRISC II) trials evaluated the potential benefit of the prolonged administration of an LMWH after hospital discharge. The first 3 of these trials did not show a benefit of treatment beyond the acute phase. In the FRISC trial, doses of dalteparin were administered between 6 days and 35 to 45 days; in FRIC, patients were rerandomized after the initial 6-day treatment period to receive dalteparin for an additional 40 days; and the outpatient treatment period lasted 5 to 6 weeks in TIMI 11B and 1 week in the FRAXIS trial. The FRISC II trial used a different study design. Dalteparin was administered to all patients for a minimum of 5 days ⁽²²³⁾. Patients were subsequently randomized to receive placebo or the continued administration of dalteparin twice a day for up to 90 days. Analysis of the results from the time of randomization showed a significant reduction with dalteparin in the composite end point of death or MI at 30 days (3.1% vs. 5.9%, p = 0.002) but not at 3 months (6.7% vs. 8.0%, p = 0.17). The composite of death, MI, or revascularization during the total treatment period was reduced at 3 months (29.1% vs. 33.4%, p = 0.031). The benefits of prolonged dalteparin administration were limited to patients who were managed medically and to patients with elevated TnT levels at baseline. These results may make a case for the prolonged use of an LMWH in selected patients who are managed medically or in whom angiography is delayed.

d. Hirudin and Other Direct Thrombin Inhibitors
Hirudin, the prototype of the direct thrombin inhibitors, has been extensively studied. The GUSTO-IIb trial randomly assigned 12,142 patients to 72 h of therapy with either intravenous hirudin or UFH ⁽²²⁴⁾. Patients were stratified according to the presence of ST-segment elevation on the baseline ECG (4,131 patients) or its absence (8,011 patients). The primary end point of death, nonfatal MI, or reinfarction at 30 days occurred in 9.8% of the UFH group vs. 8.9% of the hirudin group (odds ratio [OR] 0.89, p = 0.058). For patients without ST-segment elevation, the rates were 9.1% and 8.3%, respectively (OR 0.90, p = 0.22). At 24 h, the risk of death or MI was significantly lower in the patients who received hirudin than in those who received UFH (2.1% vs. 1.3%, p = 0.001). However, the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial of hirudin as adjunctive therapy to thrombolytic therapy in patients with STEMI showed no benefit of the drug over UFH either during study drug infusion or later ⁽²²⁵⁾. The GUSTO-IIb and TIMI 9B trials used hirudin doses of 0.1 mg per kg bolus and 0.1 mg · kg^-1 · h^-1 infusion for 3 to 5 days after the documentation of excess bleeding with the higher doses used in the GUSTO-IIA and TIMI 9A trials (0.6 mg per kg bolus and 0.2 mg · kg^-1 · h^-1 infusion) ^(224,226).

The Organization to Assess Strategies for Ischemic Syndromes (OASIS) program evaluated hirudin in patients with UA or non-Q-wave MI. OASIS 1 ⁽²²⁷⁾ was a pilot trial of 909 patients that compared the low hirudin dose of 0.1 mg per h infusion and the medium hirudin dose of 0.15 mg per h infusion with UFH. The latter dose provided the best results, with a reduction in the rate of death, MI, or refractory angina at 7 days (6.5% with UFH vs. 3.3% with hirudin, p = 0.047). This medium dose was used in the large OASIS 2 ⁽²²⁸⁾ trial that consisted of 10,141 patients with UA/NSTEMI who were randomized to receive UFH (5000 IU bolus plus 15 U · kg^-1 · h^-1) or recombinant hirudin (0.4 mg per kg bolus and 0.15 mg · kg^-1 · h^-1) infusion for 72 h. The primary