Pharmacoinvasive Management of Acute Coronary Syndrome in the Setting of Percutaneous Coronary Intervention: Evidence-Based, Sit

Over the past decade, impressive reductions in mortality, reinfarction and length of hospital stay have been reported in large-scale studies of patients with acute coronary syndrome (ACS). Despite these advances, substantial challenges remain in identifying the optimal combination of therapeutic agents [e.g., low molecular weight heparins (LMWHs) or unfractionated heparin (UFH), ADP receptor antagonists and glycoprotein (GP) IIb/IIIa inhibitors] that will maximize outcomes while minimizing drug-related adverse events in patients with ACS. As a result of clinical trials published since the March 2002 release of the updated American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for Management of non-ST elevation myocardial infarction (NSTEMI), the landscape for managing patients with ACS has shifted in a number of important ways (Table 1). First, increased emphasis has been placed on the concept that pharmacological and interventional strategies should be risk-directed. In this vein, some experts have proposed adoption of a risk assessment/stratification approach to ACS management. In this model, specific clinical, electrocardiographic, and/or laboratory features modulate aggressiveness of both medical therapy and the propensity to perform percutaneous coronary intervention (PCI) in patients with ACS. The 2002 ACC/AHA ACS Guidelines provided provisional information on how to integrate a strategy of early catheterization and revascularization with the use of LMWH and GP IIb/IIIa inhibitors because few data were available regarding combined use when the guidelines were issued. The main focus of the Cardiac Catheterization and Antithrombotic Therapy and in the Hospital (CATH) Panel, then, was to bridge these gaps and synthesize a rational and evidence-supported approach to integrating the use of new antithrombin inhibitors, new antiplatelet agents and an invasive strategy of care, specifically evaluating the use of enoxaparin with early catheterization and revascularization, with concomitant platelet GP IIb/IIIa inhibition. High-risk criteria that support more aggressive medical therapy (i.e., addition of a small molecule GP IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin, and in some cases, clopidogrel) in ACS that would direct clinicians toward early catheterization and revascularization as the dominant modality for patients with ACS include, but are not limited to, the presence of one or more of the following: 1) elevated cardiac markers (troponin, CK-MB, myoglobin); 2) elevated markers of inflammation (C-reactive protein > 3 mg/L); 3) age older than 65 years; 4) presence of ST-T wave changes; 5) TIMI Risk Score >= 5; 5) presence of diabetes; and/or 6) refractory symptoms/electrocardiographic (ECG) changes despite aggressive/maximal medical therapy (Table 2). Additional factors that may suggest the need for a more intensive approach include the presence of such comorbid conditions as heart failure, prior myocardial infarction (MI), previous coronary artery bypass graft (CABG) or LV dysfunction, and the presence of other co-existing risk factors, which, at the clinician’s discretion, suggest that maximally intensive pharmacotherapeutic approaches combined with interventional modalities will yield optimal patient outcomes. Patients with advanced renal disease, while at higher risk, must be approached cautiously given the risks of contrast-induced nephropathy. When serum creatinine is greater than 4.0 mg/dl, alternative strategies may need to be considered. Quantitative ECG analysis focusing on cumulative ST-T segment burden also may be useful for risk-stratifying patients who will derive greater benefit from aggressive management. Table 2. High-risk features and treatment trigger criteria for acute coronary syndromes: Risk-directed therapy and the sliding scale and hierarchy of care options Absolute treatment triggers, defined as high-risk features that support intensification and amplification of medical/pharmacological management or early revascularization (any one of the following): • Elevated cardiac marker (troponin, CK-MB, > myoglobin) • Elevated C-reactive protein (CRP > 3 mg/L) • Diabetes • Age > 65 years • ST-T wave segment changes • TIMI risk score >= 5 • Refractory symptoms/ECG changes despite aggressive/maximal medical therapy Relative treatment triggers, defined as additional features that support intensification and amplification of medical/pharmacological management or that support interventional strategy in acute coronary syndromes: • Prior coronary artery bypass graft • Prior myocardial infarction • Left ventricular dysfunction • Heart failure • Other co-existing risk factors, which, at the clinician’s discretion, suggest that maximally intensive pharmacotherapeutic approaches combined with interventional modalities will yield optimal patient outcomes When one considers percutaneous interventional approaches (angioplasty and stenting) in addition to the spectrum of pharmacologic options available for establishing coronary reperfusion, the decision-making process for providers at all levels (e.g., emergency physicians, medical cardiologists and interventionalists) becomes even more difficult. Regardless of the modality of revascularization used, there are a number of pathophysiological, pharmacological and clinical issues that must be factored into the efficacy and safety equation evaluating optimal approaches to ACS management. These include macro- and microvascular perfusion, recurrent ischemia, reinfarction, ability to modulate inflammatory responses, reducing the risk of intracranial hemorrhage and other major bleeding complications, and constructing regimens that reduce thrombus formation or propagation at the interface of inflammation and coagulation. Optimizing evaluation and management of patients with suspected ACS who do not manifest the electrocardiographic features of STEMI has been a recent focus of intense study and controversy. The debate has centered on optimal means of risk stratification, aggressiveness of medical therapy tied to assigned risk and the overall need and urgency of interventional management and revascularization. Updated guidelines published by the ACC/AHA provide recommendations to address these issues. The CATH Panel has focused on additional refinements and updating these pharmacological strategies, with a special focus on integrating the use of enoxaparin. With these clinical controversies and treatment options in clear focus, the CATH Clinical Consensus Panel and Scientific Roundtable was assembled for the purpose of critically evaluating recent clinical trial data; generating detailed protocols for patients with NSTE-ACS; and finally, outlining an evidence-based strategy that is site-, specialty-, and spectrum-of-care specific and that distinguishes among pharmacological and/or invasive interventions based on risk-group stratification for maximizing outcomes in patients with ACS. The CATH Clinical Consensus Panel. The CATH Clinical Consensus Panel & Scientific Roundtable assembled on March 8, 2003. The primary purpose of the CATH Panel was to assemble a group of interventional cardiologists-clinicians, academic scholars and clinical investigators to produce an evidence-based consensus document focusing on pharmacological therapy for ACS, with an emphasis on antithrombotic and antiplatelet therapy in the setting of PCI. To achieve this goal, the panel reviewed, discussed and analyzed more than 50 clinical trials and guideline statements. The Panel then formulated, using an interactive and consensus-oriented process, the evidence-based recommendations and guidelines contained in this report. The Panel entered the consensus-generating process with the full understanding that results from large, definitive trials eventually will be required to generate confirmatory evidence identifying the most outcome-effective strategies for ACS management. However, there was also consensus among Panel members that a sufficient quantity of well-designed investigations and expert consensus statements have become available to generate evidence-based protocols and treatment recommendations which, if applied in the real world setting, will enhance outcomes in ACS. Despite availability of evidence-based guidelines issued by the AHA/ACC, identifying management strategies for ACS is a complex and frequently debated topic, with some interventionalists suggesting there are sufficient data to support conversion from UFH to enoxaparin as the foundation anticoagulant in most patient subsets with ACS and STEMI. Similar controversies exist concerning the role of GP IIb/IIIa inhibitors in patients with ACS who are not undergoing cardiac catheterization, the timing of clopidogrel administration in patients undergoing PCI and the dosing of enoxaparin for ACS patients undergoing PCI. Finally, although beyond the scope of this consensus report, the importance of statins, ACE inhibitors and beta-blockers as part of a comprehensive cardioprotective strategy for patients with coronary heart disease should also be noted. Part of the Panel’s challenge identifying outcome-optimizing approaches for patients with ACS is the sheer number and various combinations of possible medical and procedural options available for decreasing morbidity, reducing the need for repeat revascularization procedures and hospitalization, and lowering mortality rates in this patient population. Because cardiovascular therapy in the setting of ACS is a vast and complex subject, the CATH Panel focused on those therapeutic areas in which the most important changes related to pharmacological management in the setting of PCI are occurring, among them: 1) the expanding role of LMWHs, and in particular enoxaparin as a foundation agent in antithrombotic regimens that might also include some combination of aspirin, oral antiplatelet drugs and GP IIb/IIIa inhibitors; 2) identification of high-risk features and treatment trigger points that support either more intensive medical therapy for ACS or the need for PCI; and 3) recognition that ACS management must be tailored to the capabilities and specialty services offered at individual institutions. Increasing evidence supporting the benefits of interventional management strategies in high-risk patients with ACS has been accompanied by the realization that a significant percentage of such patients in the United States do not have immediate access to facilities where cardiac catheterization, PCI and/or CABG services are available. As a result, risk-directed care of ACS must take into account such site-specific features, as well as the availability of clinical subspecialists (medical cardiologists, interventional cardiologists, cardiothoracic surgeons) and their capacities for executing partial versus complete spectrum-of-care services for this patient population. Acknowledging these realities will yield management protocols and treatment guidelines that are customized for individual institutions and practice settings (Table 3). To account for the full site-, specialty- and spectrum-of-care issues in ACS management in their recommendations, the CATH Panel issued specific therapeutic guidelines for each of the 3 major clinical zones (emergency department, cardiac catheterization laboratory and post-catheterization stepdown unit) in which patients with NSTE-ACS are managed. ACS (NSTEMI and unstable angina): Current management options. Perhaps one of the most important aspects of managing patients with acute coronary ischemic syndromes is the ability to risk-stratify patients into those individuals who will benefit most from either pharmacological or an early invasive strategy. Although a number of risk-stratification tools have been suggested by clinical experts and associations, the TIMI Risk Factor Score has emerged as one of the most widely accepted approaches to date for identifying patients who are most likely to benefit from specific strategies.1 (Table 4). The TIMI Risk Score is derived from the sum of the following clinical parameters, each assigned a value of one point: 1) diagnostic elevation of cardiac markers; 2) history of three or more conventional cardiac risk factors (e.g., diabetes, smoking, elevated LDL cholesterol, hypertension, family history of premature CAD); 3) age 65 years or older; 4) known coronary artery disease (CAD), defined as documented 50% or greater stenosis in at least one major coronary artery; 5) ASA use within one week of presentation; 6) two or more episodes of resting angina during the previous 24 hours prior to presentation; and 7) new ST-segment deviation (persistent depression or transient elevation not meeting fibrinolytic criteria) of 0.5 mm or greater in limb and/or precordial leads.1 As the number of risk factors increases from 0/1 to 5/7, the risk of death, MI or urgent revascularization within 14 days increases from 4.7% to 40.9% in a stepwise fashion. The TIMI Risk Score was derived from data available from the TIMI-11B trial2 and its predictive value has been validated in at least 3 additional trials: Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events (ESSENCE);3 Treat Angina with aggrastat + determine Cost of Therapy with an Invasive or Conservative Strategy (TACTICS)-TIMI4,18 and Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS).5 From a clinical, risk-directed management perspective, patients with ACS appear to derive progressively greater benefit from such pharmacologic therapies as enoxaparin2,3 and platelet GP IIb/IIIa inhibitors,6 as well as an interventional strategy4 with increasing TIMI risk score.1 The CATH Panel evaluated the usefulness of the TIMI Risk Score and also considered other absolute, high-risk features that guide: 1) the intensity of medical/pharmacological therapy in ACS; and 2) the propensity to manage ACS patients with an interventional strategy. It was concluded that no single model or risk factor is 100% predictive of adverse outcomes, nor is it predictive of the degree of incremental benefit accruing from PCI in any individual patient. However, the Panel did identify a number of absolute and relative high-risk features that could be used to facilitate risk-directed management of patients with ACS (Table 2). Invasive versus medical therapy in NSTE-ACS. The syndrome of unstable angina and MI without ST-elevation accounts for about 1.4 million hospital admissions annually in the United States. As discussed in previous sections, until recently, therapy has focused primarily on medical management using a combination of antianginal agents and antithrombotic agents. Recent studies have attempted to evaluate and compare early invasive and conservative strategies in patients with unstable coronary syndromes treated with GP IIb/IIIa inhibitors.4 The importance of an invasive strategy is enhanced by the consistent findings across 3 trials, each of which employs a different antithrombin therapy and use of GP IIb/IIIa inhibitors.7,8 The FRISC II (Fragmin During Instability in Coronary Artery Disease) trial compared 3 months of dalteparin versus placebo and compared the use of early catheterization and revascularization to a conservative strategy in a second randomization in a 2 x 2 design. At 6 months, the composite of death or acute MI was decreased by early catheterization and revascularization from 12.1% to 9.4% compared to those managed conservatively, despite a high rate of early crossover from the noninvasive to the invasive strategy (p = 0.031).9 Dalteparin decreased adverse coronary events during the 3-month administration primarily in patients who received conservative use of PCI. It was further observed that there was no benefit from the 3-month dalteparin administration in patients who were in the noninvasive segment of the study. The TACTICS Thrombolysis in Myocardial Infarction-18 (TACTICS TIMI-18) Investigators enrolled 2,220 patients with unstable angina and MI without ST-segment elevation who had ST-segment or T-wave changes, elevated levels of cardiac markers, a history of coronary artery disease, or all 3 findings.4 All patients were treated with aspirin, heparin and tirofiban. Patients were randomly assigned to an early invasive strategy, in which routine catheterization was performed as early as 4 hours and no later than 48 hours after presentation and revascularization was performed as appropriate, or to a more conservative (selectively invasive) strategy, in which catheterization was performed only if the patient had objective evidence of recurrent ischemia or abnormal stress test. The primary endpoint was a composite of death, nonfatal MI and rehospitalization for ACS at 6 months. At 6 months, the rate of the primary endpoint was 15.9% with the use of the early invasive strategy and 19.4% with the use of the conservative strategy [odds ratio (OR), 0.78; 95% confidence interval (CI), 0.62–0.97; p = 0.025]. The rate of death or non-fatal MI at 6 months was similarly reduced (7.3% versus 9.5%; OR, 0.74; 95% CI, 0.54–1.00; p 5 (OR, 0.55) or a positive serum troponin level (OR, 0.52). Two additional studies, VINO and ISAR-COOL,10,11 further support the use of an early invasive evaluation in the setting of ACS. The Value of First Day Angiography/Angioplasty In Evolving Non-ST Segment Elevation Myocardial Infarction: An Open Multicenter Randomized Trial (The VINO Study) evaluated a cohort of 131 patients with confirmed NSTEMI randomized within 24 hours of last rest chest pain to either first day angiography or early conservative treatment (angiography only after recurrent or stress-induced myocardial ischemia). On the first day, in the angiography group, PCI of the infarct-related artery was performed in 47% and bypass surgery in 35%. In the conservative group, 55% underwent angiography, 10% PCI and 30% bypass surgery within 6 months. The primary endpoint (death/reinfarction) at 6 months occurred in 6.2% versus 22.3%, respectively (p Table 3. Acute coronary syndrome (NSTE-ACS): Site-, specialty-, and spectrum-of-care strategies for outcome-effective management: CATH Clinical Consensus Panel Guidelines and Recommendations Pharmacoinvasive Management of ACS in the Emergency Department: Initiate Risk Stratification and Pharmacological Antithrombotic Management A) High-risk features present: NSTE-ACS patients with high-risk features and/or treatment trigger criteria will benefit from an interventional strategy, which is the evidence-based management option of choice for this subgroup of ACS patients. The antithrombotic regimen for NSTE-ACS patients for whom coronary angiography is planned should include: • Aspirin 162–325 mg PO (immediately) • Clopidogrel 300 mg loading dose (only if it is confirmed that patient is not a CABG candidate; if CABG is possible, clopidogrel should be withheld until coronary anatomy is defined at time of catheterization) • Enoxaparin 30 mg IV bolus (optional1) followed by 1 mg/kg SC q 12 hr (alternative: UFH)2 As dictated by clinical presentation and need to implement appropriate measures for acute medical management of ischemic chest pain, pulmonary edema, hypertension and other hemodynamic abnormalities in the emergency department, the following agents may be initiated according to clinical protocols: • Nitroglycerin IV/SC/TC/SL • Morphine sulfate IV PLUS (GP IIb/IIIa inhibitor) If patient is admitted from the emergency department to the hospital and it is anticipated that cardiac catheterization will be performed during the hospitalization, the emergency physician, in consultation with the interventional cardiologist, should initiate antiplatelet therapy with the GP IIb/IIIa receptor antagonist, eptifibatide, which should be added to the core regimen above: • Eptifibatide 180 µg/kg IV bolus, followed by 2.0 µg/kg/min infusion for 18–72 hr (alternative: tirofiban 0.4 µg/kg loading dose given over 30 minutes, followed by 0.1 µg/kg/min infusion for 48 hr) OR If patient is to be transferred directly from the emergency department to the cardiac catheterization laboratory to undergo cardiac catheterization for evaluation of coronary architecture and possible PCI, abciximab may be administered in the cardiac catheterization laboratory. • Abciximab [0.25 mg/kg bolus IV, followed by 0.125 µg/kg/min (maximum, 10 µg/min) infusion for 12 hr] • Alternative GP IIb/IIIa inhibitor for primary PCI: Eptifibatide 180 µg/kg IV bolus x 2, 10 minutes apart, followed by 2.0 µg/kg/min infusion for 18–72 hr B) No high-risk features: For the NSTE-ACS patient who does not have high-risk features or treatment trigger criteria3 supporting inclusion of small molecule GP IIb/IIIa receptor antagonist, and in whom cardiac catheterization is not planned, initial management would include: • Aspirin 162–325 mg PO • Clopidogrel 300 mg loading dose4 • Enoxaparin 30 mg IV bolus (optional1) followed by 1 mg/kg SC q 12 hr (alternative: UFH)2 As dictated by clinical presentation and need to implement appropriate measures for acute medical management of ischemic chest pain, pulmonary edema, hypertension and other hemodynamic abnormalities in the emergency department, the following agents may be initiated according to clinical protocols: • Nitroglycerin IV/SC/TC/SL • Morphine sulfate IV Cardiac Catheterization Laboratory—Antithrombotic Therapy for PCI NSTE-ACS patients with moderate- to high-risk features and/or aggressive treatment trigger points should undergo invasive assessment of their coronary anatomy. The pharmacological foundation regimen in those patients should include the following: • Aspirin 162–325 mg PO (immediately, or in the emergency department) • Clopidogrel 300 mg loading dose (to be initiated upstream only if it is confirmed that patient is not a CABG candidate; if CABG remains a therapeutic option, clopidogrel should be held until coronary anatomy is defined by cardiac catheterization) PLUS (LMWH)2 • Enoxaparin 30 mg IV bolus (optional1) followed by 1 mg/kg SC q 12 hr (for cardiac catheterization/PCI considerations, see dosing algorithm below),5,6,7 initiated prior to catheterization upon initial presentation PLUS (GP IIb/IIIa antagonist)8 At PCI (if not already initiated in the ED): • Abciximab [0.25 mg/kg bolus IV, followed by 0.125 µg/kg/min (max 10 µg/min) infusion for 12 hr] OR • Eptifibatide 180 µg/kg IV bolus x 2, 10 minutes apart, followed by 2.0 µg/kg/min infusion for 18 hr (alternative: tirofiban 0.4 µg/kg loading dose, followed by 0.1 µg/kg/min infusion for 48 hr) Post Cardiac-Catheterization Inpatient Care (Step-Down, Coronary Care/Medical Intensive Care Unit) Post-cardiac catheterization, subsequent inpatient pharmacological management will depend upon coronary anatomy findings at time of catheterization, whether or not stent insertion has been successfully completed, and/or if the patient has coronary anatomy that is conducive to and is scheduled for CABG. 1) In a patient who has undergone cardiac catheterization and is found to have normal coronary anatomy: • Aspirin 162 mg PO QD (for insignificant CAD or for cardioprotection in patients with significant CAD risk factors) Enoxaparin dosing algorithm5,6,7 for PCI Therapeutic Anti-Xa Levels. To ensure that ACS patients promptly achieve therapeutic anti-Xa levels, a 30 mg IV loading dose of enoxaparin is recommended, followed immediately by administration of 1 mg/kg SC q 12 hr. Therapeutic anti-Xa levels also are achieved after >= 2 doses of enoxaparin 1 mg/kg SC q 12 hr have been administered, even in the absence of an initial loading dose. If an initial 30 mg IV loading dose of enoxaparin has been administered, or >= 2 doses of SC enoxaparin have been administered (without IV loading dose): • If procedure is performed within 8 hours of the last SC dose, no additional enoxaparin needs to be administered. • If procedure is performed at a point within 8-12 hours of the last SC dose, 0.3 mg/kg enoxaparin IV should be administered in the catheterization laboratory. If an initial 30 mg IV dose of enoxaparin has not been administered and if only one dose of SC enoxaparin has been administered (in a patient without an IV loading dose): • At time of procedure, patient should receive a booster dose of 0.3 mg/kg prior to catheterization/PCI. The ENOX clotting time may be measured in such patients; if it is found to be > 260 seconds, the booster dose may be withheld. If no enoxaparin has been previously administered: • At time of procedure, 1.0 mg/kg enoxaparin IV should be administered in the catheterization laboratory if a GP IIb/IIIa inhibitor is not given; 0.75 mg/kg enoxaparin IV should be administered when a GP IIb/IIIa will be used. Sheath removal. Timing of sheath removal depends on a number of factors, among them, whether or not a closure device is employed and time and route of last enoxaparin dose: • Sheath can be removed 6–8 hours after the last SC dose of enoxaparin without a closure device, or immediately if a closure device was employed. • Sheath can be removed 4 hours after the 0.3 mg/kg IV supplemental dose for the 8–12 hour group, as well as after the 1.0 mg/kg IV (0.75 mg/kg with a GP IIb/IIIa inhibitor) for the patients undergoing PCI > 12 hours after their last SC dose or who have not received any pretreatment. 2) In a patient who has undergone cardiac catheterization, has had stent insertion, and is not going to CABG: • Aspirin 162 mg PO QD • Clopidogrel 75 mg PO QD for 1 year (assumes that 300 mg loading dose was already given) • GP IIb/IIIa inhibitor: (continue 12 hours for abciximab; 18 hours for eptifibatide or tirofiban) As dictated by the presence of ischemic symptoms, abnormal hemodynamic parameters, cardiac risk factors, hypertension, diabetes, and/or left ventricular dysfunction, the following agents, if not contraindicated, should be considered for administration during the acute hospitalization, and when indicated, should be continued for cardioprotection and/or management of symptoms following discharge: • Statin therapy (within 96 hours of acute ischemic event) • ACE inhibitors • Beta-blockers • Nitrate therapy 3) In a patient with anatomy appropriate for surgical revascularization, who is scheduled for and awaiting CABG: • Aspirin 325 mg PO QD • Clopidogrel (should be discontinued, with a plan to restart clopidogrel at 75 mg PO QD the day following surgery, provided there is no bleeding). • GP IIb/IIIa (eptifibatide or tirofiban continued up to 4–6 hours before induction) • Enoxaparin (discontinue 24 hours before surgery) OR • UFH (continue up to the time of surgery) As dictated by the presence of ischemic symptoms, abnormal hemodynamic parameters, cardiac risk factors, hypertension, diabetes, and/or left ventricular dysfunction, the following agents, if not contraindicated, should be considered for administration during the acute hospitalization, and when indicated, should be continued for cardioprotection and/or management of symptoms following discharge: • Statin therapy (within 96 hours of acute ischemic event) • ACE inhibitors • Beta-blockers • Nitrate therapy No Initial Catheterization Low-risk feature patients with NSTE-ACS who are are not undergoing cardiac catheterization and who are being managed medically in the hospital: • Aspirin 162 mg PO QD • Clopidogrel 75 mg PO QD • Enoxaparin 1 mg/kg SC q 12 hr (or UFH) x 3–8 days As dictated by the presence of ischemic symptoms, abnormal hemodynamic parameters, cardiac risk factors, hypertension, diabetes, and/or left ventricular dysfunction, the following agents, if not contraindicated, should be considered for administration during the acute hospitalization, and when indicated, should be continued for cardioprotection and/or management of symptoms following discharge: • Statin therapy (within 96 hours of acute ischemic event) • ACE inhibitors • Beta-blockers • Nitrate therapy High-risk feature patients with NSTE-ACS who did not undergo cardiac catheterization initially, who are being managed medically in the hospital, but in whom cardiac catheterization prior to discharge is planned: • Aspirin 162 mg PO QD • Enoxaparin 30 mg IV (optional), followed by 1 mg/kg SC q 12 hr (or UFH) x 3-8 days • Eptifibatide 180 µg/kg IV bolus, followed by 2.0 µg/kg/min infusion for 18–72 hours (alternative: tirofiban) As dictated by the presence of ischemic symptoms, abnormal hemodynamic parameters, cardiac risk factors, hypertension, diabetes, and/or left ventricular dysfunction, the following agents, if not contraindicated, should be considered for administration during the acute hospitalization, and when indicated, should be continued for cardioprotection and/or management of symptoms following discharge: • Statin therapy (within 96 hours of acute ischemic event) • ACE inhibitors • Beta-blockers • Nitrate therapy TABLE 3 KEY 1) From a pharmacodynamic perspective, administration of a 30 mg IV bolus immediately prior to the first 1 mg/kg SC dose of enoxaparin permits the patient to promptly achieve therapeutic factor anti-Xa levels; therefore, when prompt/immediate PCI is possible, administration of 30 mg IV enoxaparin bolus (followed by 1 mg/kg SC q 12 hr) is recommended by the CATH Consensus Panel. When PCI is likely to be delayed, the possible advantages of a 30 mg IV bolus of enoxaparin are less well defined. It should be noted that the risk of bleeding associated with administration of an IV enoxaparin (30 mg) bolus dose plus a GP IIb/IIIa inhibitor is not known; however, the risk of bleeding associated with combined use of enoxaparin 1 mg/kg SC 12 hr (i.e., no IV bolus) plus GP IIb/IIIa inhibitors has been shown to be comparable to, and in some studies lower than, bleeding resulting from combined use of unfractionated heparin (UFH) plus GP IIb/IIIa receptor antagonists. Use of an initial enoxaparin 30 mg IV bolus is not recommended in patients > age 75 who are concomitantly being treated with thrombolytics or GP IIb/IIIa inhibitors. Continued in Parts II and III

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