Pharmacoinvasive Management of Acute Coronary Syndrome:
Incorporating the 2007 ACC/AHA Guidelines

Every year, more than 1 million patients are admitted to a hospital with a diagnosis of unstable angina or non-ST-elevation myocardial infarction (UA/NSTEMI).¹ Relative to acute ST-elevation myocardial infarction (STEMI), patients with UA/NSTEMI have a slightly higher 1-year mortality rate,² and constitute a significantly larger proportion of patients with acute coronary syndromes (ACS).³ During the course of their hospitalization, these patients will interact with many different healthcare professionals, be subjected to many different drugs, diagnostic and invasive procedures, and be moved through several different hospital units before being discharged on multiple different medications. While the 2002 American College of Cardiology/American Heart Association Guidelines (ACC/AHA) provided a foundation for management of patients with UA/NSTEMI, a host of recent, prospective, randomized, clinical therapeutic trials of some already-approved antithrombotics as well as newer agents have been published or presented at international meetings involving more than 75,000 patients. In recognition of the fast-moving pace of scientific discovery, the 2002 guidelines were updated and published in late 2007.⁴ In addition, several recent large clinical trials have presented new options above and beyond those presented in the 2004 American College of Cardiology/American Heart Association Guidelines (ACC/AHA) for the management of patients with STEMI.⁵
However, despite the new information and updated guidelines, substantial challenges remain in identifying the optimal combination of therapeutic agents that will maximize benefits while minimizing drug-related adverse events in the individual patient with NSTEMI. The decision-making process in terms of choosing among the spectrum of pharmacologic options (e.g., low-molecularweight heparins (LMWHs), unfractionated heparin [UFH], direct antithrombins [DTI], indirect factor-Xa inhibitors, P2Y₁₂ – adenosine diphosphate (ADP) receptor blockers and glycoprotein [GP] IIb/IIIa inhibitors), and the optimal timing for invasive catheterization and percutaneous interventional (PCI) approaches is complicated by the large number of “stakeholders”: emergency physicians, medical cardiologists, interventionalists, cardiac surgeons, nurse practitioners and nurses. Not infrequently, the choices appealing to emergency department providers may be different from the choices interventional cardiologists will make.

CARDIAC CATHETERIZATION AND ANTITHROMBOTIC THERAPY IN THE HOSPITAL CLINICAL CONSENSUS PANEL
The third Cardiac Catheterization and Antithrombotic Therapy in the Hospital (CATH) Clinical Consensus Panel & Scientific Roundtable assembled on November 2, 2007. With the above-mentioned clinical controversies and treatment options as targets, the purpose of the Panel was to critically evaluate recent clinical trial data; elaborate a rational and evidencebased approach to integrating the published and or presented information relating to the direct thrombin inhibitors, indirect and direct anti-Xa agents, and new antiplatelet agents; develop a strategy for invasive care; and outline a site-, specialty- and spectrum-of-care-specific, evidence-based strategy that distinguishes among pharmacological and/or invasive interventions based on risk-group stratification for maximizing outcomes in patients with NSTE-ACS.
The CATH Panel focused on those therapeutic areas in which the most important changes are occurring related to pharmacological management in the setting of PCI: 1) the expanding array of antithrombins such as the LMWH enoxaparin, the indirect, selective Xa inhibitor fondaparinux and the direct selective thrombin inhibitor bivalirudin, including combination with platelet inhibitors: 2) use of aspirin, oral antiplatelet drugs clopidogrel, prasugrel, and/or GP IIb/IIIa inhibitors; 3) identification of high-risk features and treatment trigger points that support either more intensive medical therapy or the need for PCI; and 4) recognition that utilization and choice of agents rests to a large extent on the balance between the benefit of reducing recurrent ischemic events relative to the risks incurred from increasing major and/or minor bleeding events.
Surprisingly, a significant percentage of patients in the United States still do not have immediate access to facilities where cardiac catheterization, PCI and/or coronary artery bypass graft surgery (CABG) services are available. As a result, risk-directed care must also take into account site-specific features as well as the availability of clinical subspecialists. Acknowledging these realities, the CATH Panel (vide infra) has reviewed several recent trials spanning the spectrum from conservative medical therapy to invasive percutaneous therapies, as well as recent trials in STEMI that provide new insights regarding antithrombotic therapy in ACS. The CATH Panel focused on the specific therapeutic issues for each of the three major clinical zones (emergency department, cardiac catheterization laboratory and post catheterization stepdown unit) in which patients with NSTE-ACS are managed.

ROLE OF RISK STRATIFICATION
Because of the broad spectrum of patients presenting with UA/NSTEMI or STEMI ACS, there is no “one-size-fits-all” therapeutic strategy that can be adopted. To assist the clinician in correlating the intensity of the treatment plan with the acuity of the patient, several risk stratification models have been presented in the 2007 ACC/AHA guideline updates. Although the 2002 guidelines recommended an early invasive strategy (diagnostic angiography and revascularization) for UA/NSTEMI, the current guidelines differentiate between high- and low-risk patients with UA/NSTEMI. Risk scores may be used to integrate multiple clinical factors that determine risk. Troponin (Tn) biomarkers of cardiac damage and B-type natriuretic peptide (BNP) markers for assessment of cardiac risk may be useful in risk stratification when integrated into an overall clinical risk score. Perhaps one of the most important aspects of managing patients with NSTE-ACS 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 Thrombolysis in Myocardial Infarction (TIMI) Risk 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.⁶ 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 3 or more conventional cardiac risk factors (e.g., diabetes, smoking, elevated low-density lipoprotein cholesterol, hypertension or family history of premature coronary artery disease [CAD]); 3) age ≥ 65 years; 4) known CAD, defined as documented ≥ 50% stenosis in at least 1 major coronary artery; 5) aspirin use within 1 week of presentation; 6) 2 or more episodes of resting angina during the previous 24 hours prior to presentation; and 7) new STsegment deviation (persistent depression or transient elevation not meeting fibrinolytic criteria) of ³ 0.5 mm in limb and/or precordial leads.⁶ 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.
More recently, additional makers providing prognostic information in patients with ACS, such as C-reactive protein (CRP), BNP and renal dysfunction, have been identified in addition to cardiac Tn.^7,8 In patients with ACS, BNP and Nterminal prohormone brain natriuretic peptide (NT-proBNP) are prognostic for mortality and new heart failure, but are less consistently so for recurrent MI.⁹ However, until specific therapeutic recommendations can be made, the routine use of BNP and NT-proBNP in all patients with suspected ACS cannot be recommended.
BNP has been added to the guidelines as a biomarker test that can be considered to supplement global risk assessment in ACS patients based upon consistent data from more than 10 clinical studies.

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 or other anticoagulant, and clopidogrel), or that direct clinicians toward early catheterization and revascularization as the dominant modality for patients with ACS are outlined in Table 1. Additional factors to consider include the presence of such comorbid conditions as heart failure, prior MI, previous CABG and left ventricular (LV) dysfunction. Patients with advanced renal disease, clearly a group at higher risk for recurrent ischemic events, must be approached cautiously given the risks of contrast-induced nephropathy and bleeding. When serum creatine levels are > 4.0 mg/dL, alternative strategies may need to be considered.

ROLE OF EARLY INVASIVE, SELECTIVE INVASIVE, OR CONSERVATIVE THERAPY
In parallel with the logic that the intensity of the pharmacologic medical therapy should correlate with the acuity of the patient, decisions regarding the merits of an early invasive versus a conservative approach in ACS should also be “risk”-based. Initial studies evaluating the benefits of an early invasive or “anatomic” strategy as compared to a conservative or “ischemiadriven” strategy suggested that outcomes are not improved with routine catheterization and early revascularization in the absence of recurrent or provoked ischemia.^10,11 Recent studies in the past 4 years have readdressed the merits of an early invasive strategy in the setting of improved PCI techniques, optimal pharmacotherapy in both medically managed and revascularized patients and longer clinical follow up. Because trials of invasive and conservative strategies in NSTE-ACS were conducted during an era of rapid change in cardiology practice characterized by the introduction of new antithrombotic drugs and interventional techniques, direct comparison of trials completed in differentcountries comprising heterogeneous patient populations with changing definitions of MI is challenging at best. To account for these inherent differences, two meta-analyses have been reported focusing on the role of early angiography and revascularization in the management of a broad spectrum of patients.^12,13 Mehta and colleagues analyzed results from 9,212 patients randomized in TIMI-IIIb, Medicine versus Angiography in Thrombolytic Exclusion (MATE), Veterans Affairs Non–q-wave Infarction Strategies in Hospital (VANQWISH), FRISC-II, TACTICS TIMI-18, VINO and RITA-3.¹³ During a mean follow-up period of 17 months, the overall composite endpoint of death or MI was reduced from 14.4% in the conservative group to 12.2% in the invasive group (p = 0.001), driven primarily by a reduction in MI (9.4% vs. 7.3%; p < 0.001).¹³ There was a nonsignificant trend toward lower mortality with the invasive strategy (6.0% vs. 5.5%). During the initial hospitalization, there was actually a significant increase in deaths in the early-invasive group (1.1% vs. 1.8%; p = 0.007). After the initial hospitalization, however, the risk of death was 24% lower in the invasively managed patients (4.9% vs. 3.8%; p = 0.01). The meta-analysis by Hoenig and coworkers of FRISC-II, TACTICS TIMI-18, VINO, RITA-3 and ICTUS (total patients = 7,818) reached similar conclusions.¹² Early inhospital mortality overall was low, but was higher in the invasive group (1.3% vs. 0.8%; p = 0.007). The risk of a peri-procedural MI in the early-invasive group was 2-fold higher and risk of bleeding was 1.7 times higher as compared with the conservatively managed patients. However, after hospital discharge, risk of death or MI was significantly reduced by an invasive strategy at various time points. Late mortality (2 to 5 years) was significantly lower in the invasive strategy arm (6.9% vs. 9.3%; p = 0.006), in spite of including the data from ICTUS. Both meta-analyses found that benefit of the invasive strategy was confined to the highest-risk patients (i.e., Tn-positive) and that early intervention in the lower-risk patients had either a neutral or detrimental effect on outcomes. For unstable and high-risk patients, an early invasive strategy is recommended to establish and maintain normal levels of myocardial perfusion by mechanical means. Evidence favors an early intervention at intervals of less than 6 to 24 hours, rather than at intervals of 48 to 96 hours.

Early Invasive Therapy: Panel Recommendations
• Early catheterization and revascularization reduces risks of recurrent angina and the need for rehospitalization as well as MI, and possibly death, in the long term at the expense of higher rates of early mortality, periprocedural MI and bleeding in high-risk patients.
• Conversely, patients who are poor candidates for revascularization or who are at high risk for bleeding may be better off avoiding invasive therapies.
• Therapies that reduce risk of periprocedural MI such as pretreatment with clopidogrel and appropriate use of GP IIb/IIIa antagonists are also likely to improve results with an earlyinvasive approach.
• Stabilized patients with UA/NSTEMI and those at low risk may be treated conservatively at first with a noninvasive stress test, echocardiogram or radionuclide angiogram. Although PCI is beneficial in high-risk patients, it may be associated with poor outcomes in low-risk women. The success of antiplatelet and anticoagulant therapies also depends in part on the risk of death and recurrent ischemic events.
• During hospitalization for UA/NSTEMI, all patients should refrain from use of nonsteroidal antiinflammatory drugs (NSAIDs). Hormone replacement therapy should be discontinued in postmenopausal women.

COMPARISON OF THE 2007 ACC/AHA VERSUS THE EUROPEAN SOCIETY OF CARDIOLOGY UA/NSTEMI GUIDELINES

Within several months of each other, both the ACC/AHA and the European Society of Cardiology (ESC) issued new guidelines for patients with UA/NSTEMI.^4,14 Both documents were extensive revisions of guidelines last updated in 2002. The AHA/ACC Guideline Revision continued its practice of using the terms “unstable angina” (UA) and “non-ST-elevation myocardial infarction” (NSTEMI), while the ESC used the term “non-ST-segment elevation acute coronary syndrome” (NSTE-ACS). Table 2 shows some of the differences between the two guidelines.
While the ESC continued with the “traditional” classification of “Level of Evidence” (LOE) (e.g., LOE A = multiple randomized trials or meta-analysis.), the ACC/AHA used the more recently adopted system that uses “estimate of certainty of treatment effect” (e.g., LOE A = multiple [3–5] population risk strata evaluated). The ACC/AHA guidelines emphasize that a recommendation with LOE B or C does not imply that the recommendation is weak, noting that “many important clinical questions do not lend themselves to clinical trials…yet there may be very clear clinical consensus that a particular test or therapy is useful or effective”.
Both guidelines place a strong emphasis on risk stratification models and risk scores in risk assessment and decision making. The ACC/AHA guidelines cite the TIMI, GRACE and PURSUIT risk scores, while the ESC guidelines place particular emphasis on the GRACE score and its role in decision making. In general, the ACC/AHA guidelines divide many managementdecisions, particularly pharmacotherapy, into “early-invasive” and “initial-conservative” strategies, give weight in certain circumstances to more established, well-tested medications and include recommendations for numerous special patient populations. The ESC guidelines emphasize the role of biomarkers and risk score, divide management decisions into “urgent” and “nonurgent”, place a strong emphasis on bleeding complications and the prevention of bleeding, include recommendations for multiple special patient populations and also include a discussion of performance measures.
With regard to oral antiplatelet therapy, both guidelines assign the administration of aspirin a Class I - LOE = A recommendation. Both make a Class I recommendation that clopidogrel be used in aspirin-allergic or intolerant patients, though the ACC/AHA guidelines assign this a LOE = A, while the ESC guidelines assign this a LOE = B. The ACC/AHA guidelines give a Class I – LOE = A recommendation to the use of clopidogrel in addition to aspirin if an initial conservative strategy is used, and give a Class I – LOE = A recommendation to the use of either clopidogrel or a GP IIb/IIIa inhibitor if an early invasive strategy is used. In slight contrast, the ESC guidelines give a Class I – LOE = A recommendation for the use of clopidogrel in addition to aspirin in all patients, and strongly emphasize this point in the text. While both guidelines discuss the option of using a clopidogrel loading dose of 600 mg (instead of 300 mg), this option is more enthusiastically embraced in the ESC guidelines.
As noted above, the ACC/AHA guidelines give a Class I – LOC A recommendation to the use of either GP IIb/IIIa inhibitors or clopidogrel for an early invasive strategy, as well as a slightly less enthusiastic (Class IIa – LOC B) recommendation for the use of both agents for an early invasive strategy. GP IIb/IIIa inhibitors are not recommended for an initial conservative strategy and are to be considered for patients already on aspirin and clopidogrel who develop recurrent ischemia (Class IIa – LOC C). The ESC guidelines suggest the use of GP IIb/IIIa inhibitors, in addition to aspirin and clopidogrel, in intermediate- to high-risk patients (Class IIa – LOC A). In high-risk patients who have not been pretreated with a GP IIb/IIIa inhibitor who are proceeding to PCI, abciximab is more enthusiastically recommended (Class I – LOC A) in the ESC guidelines, and it is noted that eptifibatide and tirofiban are less well established in this setting (Class IIa – LOC B). Both guidelines allow for the omission of a GP IIb/IIIa inhibitor if bivalirudin is used, and both give this recommendation a Class IIa – LOC B endorsement. Neither guideline addresses the results of “ACUITY timing” (i.e., deferring a GP IIb/IIIa inhibitor until the PCI) in their recommendations.
With regard to antithrombin therapy, the ACC/AHA guidelines give a Class I recommendation to the use of all 4 current “major players” (UFH, enoxaparin, fondaparinux and bivalirudin), though they note that there are more data in support of UFH and enoxaparin (LOE A) than fondaparinux and bivalirudin (LOE B), and bivalirudin is only recommended for early-invasive strategy patients. For initial conservative-strategy patients, enoxaparin or fondaparinux are preferred over UFH (Class IIa – LOE B), and fondaparinux is preferred for conservative-strategy patients with increased risk of bleeding (Class I – LOE B). The ESC guidelines emphasize that the choice of anticoagulant depends on the initial strategy, and that the anticoagulant should be selected according to the risk of both ischemic and bleeding events. For “urgent invasive situations”, UFH (Class I – LOE C), enoxaparin (Class IIa – LOC B) and bivalirudin (Class I – LOE B) are recommended. For “nonurgent situations,” fondaparinux is recommended on the basis of the most favorable efficacy/safety profile (Class I – LOC A), with enoxaparin to be considered only if the bleeding risk is low (Class IIa – LOE B). Divergent from the ACC/AHA guidelines, they note that other LMWH agents and UFH cannot be recommended over fondaparinux due to lack of head-to-head data. Although both the ACC/AHA and ESC guidelines discuss the issue of the clopidogrel pretreatment – bivalirudin interaction in the ACUITY study, only the ACC/AHA guidelines address this in the actual recommendations, noting that for an initial invasive strategy, it is reasonable to omit upstream GP IIb/IIIa inhibitor therapy if bivalirudin is used and ONLY if at least 300 mg of clopidogrel was administered at least 6 hours earlier than the planned catheterization or PCI (Class IIa – LOC B).

FOCUS ON THE 2007 ACC/AHA GUIDELINES FOR PATIENTS WITH UA/NSTEMI ACS:
New Aspects Related to Pharmacologic Management
Bivalirudin and fondaparinux. Given the evidence supporting two new alternatives for the management of ACS, the direct thrombin inhibitor bivalirudin¹⁵ and the pentasaccharide fondaparinux¹⁶ have been incorporated into the 2007 guidelines. Both agents have a Class 1 (level of evidence = B) indication for use in addition to antiplatelet therapy, with bivalirudin used in conjunction with an invasive strategy and fondaparinux used in conjunction with a conservative strategy. Unfractionated heparin (UFH) and enoxaparin are given Class 1 indications (with LOE = A) in patients undergoing either an invasive or a conservative strategy. However, the guidelines suggest that fondaparinux would be preferred over these agents in patients at an increased risk of bleeding for whom a conservative strategy is selected. In patients with UA/NSTEMI for whom an initial conservative strategy is selected (with the possibility of converting to an invasive strategy other than CABG), enoxaparin or fondaparinux are recommended over UFH.
Clopidogrel. For patients treated invasively, the recommended duration of clopidogrel therapy has been extended for at least 1 year after drug-eluting stent placement and ideally up to 1 year with a bare-metal stent,¹⁷ or even with medical therapy.¹⁸ The new guidelines address a higher loading dose of clopidogrel. Based on recent studies using loading doses of 300, 600 or 900 mg, it was identified that a 600 mg loading dose offered a more prompt and reliable platelet inhibition than a 300 mg loading dose. There was no incremental benefit of increasing the dose beyond 600 mg to 900 mg.^19,20 More studies will be required to determine the impact of this higher dose on outcomes. Recent data from the Atorvastatin for Reduction of Myocardial Damage during Angioplasty (ARMYDA) investigators²¹ do not indicate any incremental benefit of the 600 mgloading dose if the patient is already on regular clopidogrel treatment prior to PCI. A 300 mg loading dose prior to PCI would suffice in those cases.
Glycoprotein (GP) IIb/IIIa inhibitors. Recommendations for GP IIb/IIIa inhibitors do not differ significantly from the 2002 guidelines. In the interval between guidelines there were studies suggesting that clopidogrel administration was safe and effective for PCI without the need for GP IIb/IIIa inhibitors in very low-risk patients.^22,23 As the patient’s risk increases, the administration of triple antiplatelet therapy — aspirin, clopidogrel and GP IIb/IIIa inhibitors — becomes much more important.^22,24 Thus, in higher-risk patients, the guidelines suggest the use a GP IIb/IIIa inhibitor if an invasive strategy is being followed, even if clopidogrel has been initiated. In lower-risk patients, practitioners may use one or the other, or possibly both.

Early Antithrombotic Therapy: Panel Recommendations
Platelet inhibitors
• Aspirin should be administered to patients with ACS as soon as possible (unless contraindicated) and continued indefinitely. Patients with aspirin allergy or intolerance should be treated with clopidogrel.
• Clopidogrel, in addition to aspirin, should be initiated in patients in whom either a conservative or an early invasive therapy is considered, but when the likelihood of surgical disease requiring early CABG is low. Antiplatelet therapy with clopidogrel 75 mg/day should be given for 1 year or more after receiving a drug-eluting stent. Treatment should include aspirin (162–325 mg/day) for 3 months or more after implantation of a sirolimus-eluting stent, and for 6 months after implantation of a paclitaxel-eluting stent, then continued indefinitely at 75 to 162 mg/day.
• Patients with UA/NSTEMI who are treated medically without stenting should receive aspirin (75–162 mg/day) indefinitely and clopidogrel (75 mg/day) for 1 to 12 months. Patients with UA/NSTEMI who are treated with bare-metal stents should receive aspirin (162–325 mg/day) for at least 1 month, then indefinitely at 75 to 162 mg/day, and clopidogrel 75 mg/day for 1 to 12 months.
• GP IIb/IIIa receptor antagonists – Upstream use of eptifibatide or tirofiban should be considered in high-risk patients (such as those with Tn elevation), especially if an invasive therapy is contemplated. Abciximab should not be used unless there is no appreciable delay to PCI. Abciximab can be used safely for PCI in patients who have not received upstream GP IIb/IIIa inhibitors and may be better than tirofiban in this population. GP IIb/IIIa inhibitors provide incremental benefit in patients with elevated Tn undergoing PCI, even among those pretreated with clopidogrel.
Anticoagulant therapy
• In patients treated with conservative therapy, the preferred anticoagulant may be fondaparinux, enoxaparin for 8 days or for the duration of hospitalization, or UFH for 48 hours, in that order.
• In patients treated with invasive therapy, enoxaparin or UFH-based regimens have the most supporting evidence. • For patients undergoing CABG, aspirin should be continued while clopidogrel should be stopped 5 to 7 days before, and GP IIb/IIIa inhibitors stopped 4 hours before the surgery. Enoxaparin should be stopped 12 to 24 hours prior and fondaparinux stopped 24 hours prior to CABG, and UFH should be started.
• All patients receiving intravenous (IV) GP IIb/IIIa inhibitors must also receive concomitant UFH or another antithrombotic agent.
• Bivalirudin can be used as an alternative anticoagulant for a rapid invasive strategy (in ACUITY the median time from antithrombotic study drug to angiography was 4.1 [1.4–20]) on a background of oral antiplatelet therapy.
• Special attention to drug dosing and altered pharmacodynamics is warranted while treating the elderly and patients with renal impairment. In the CRUSADE quality initiative, errors in dosing were associated with bleeding.^25,26 Appropriate dosing of UFH, enoxaparin and GP IIb/IIIa inhibitors and bivalirudin is required. The factors that determine an adjustment in dose are age, weight and creatine clearance.

NEW ANTIPLATELET AGENTS IN CLINICAL DEVELOPMENT
Platelets have a crucial role in the maintenance of normal hemostasis, and disturbances of this system can result in pathological thrombus formation and vascular occlusion, culminating in cerebrovascular events, MI and UA. Adenosine diphosphate (ADP), released from both damaged vessels and erythrocytes, induces platelet aggregation via activation of the integrin GP IIb/IIIa and subsequent binding of fibrinogen. ADP is also secreted from platelets on activation, providing positive feedback that strengthens the actions of many platelet activators. ADP mediates platelet aggregation through its action on specific receptor subtypes. These subtypes are being investigated as targets for newly developed antiplatelet agents. For example, the P2Y₁₂ protein is a chemoreceptor for ADP and is found on the surface of platelets.²⁷ While the molecular identity of this receptor is still elusive, it is the target of efficacious antithrombotic agents such as clopidogrel.²⁸ The receptor, however, has been cloned, which has facilitated the development of better antiplatelet agents to treat cardiovascular disease.
Prasugrel. One emerging agent in phase 3 trials is prasugrel, which, like clopidogrel, is a thienopyridine, but unlike clopidogrel, has a different metabolic pathway in that it takes only a single step through the P450 CYP route to become an active metabolite.²⁹ The result is an antiplatelet agent that has a quicker onset of action than clopidogrel 300 mg (1 hour vs. 6 hours). The product is not as susceptible to P450 CYP inhibition by other agents, such as the azole fungicides.²⁹ Based on phase 1 study of a 60 mg loading dose of prasugrel versus the approved 300 mg loading dose of clopidogrel in a two-way crossover design,³⁰ all prasugrel-treated patients achieved a greater than 25% inhibition of platelet aggregation compared to only 42% of clopidogrel-treated patients who achieved this level of platelet inhibition (p ≤ 0.001). In the phase 2 Joint Utilization of Medications to Block Platelets Optimally (JUMBO-TIMI 26) Trial,the mean maximum inhibition of platelet aggregation (IPA) following a loading dose of prasugrel 60 mg or clopidogrel 300 mg was 84% with prasugrel versus 49% with clopidogrel for 5 μmol/L ADP and 79% versus 35%, respectively, for 20 μmol/L ADP (p < 0.001). Response to prasugrel was more consistent compared to clopidogrel (p < 0.01) bleeding.³¹ This more consistent platelet inhibition translated into fewer ischemic events in the prasugrel treated patients in the very large TRITON-TIMI 38 trial. In this study, 13,608 patients with moderate-to-high-risk acute coronary syndromes scheduled for PCI were randomized at the time of the procedure to receive either prasugrel (a 60 mg loading dose and a 10 mg daily maintenance dose) or clopidogrel (a 300 mg loading dose and a 75 mg daily maintenance dose) for 6 to 15 months.³²
The study included patients with ischemic symptoms lasting 10 minutes or more and occurring within 72 hours prior to randomization, a TIMI Risk Score of 3 or more, and either ST-segment deviation of 1 mm or more or elevated cardiac biomarker levels. Patients with STEMI could be included within 12 hours after the onset of symptoms if primary PCI was planned, or within 14 days after treatment of an STEMI. The primary efficacy endpoint was death from cardiovascular causes, nonfatal MI or nonfatal stroke. The key safety endpoint was non-CABG TIMI major bleeding.
At a median follow up of 14.5 months, the primary efficacy endpoint occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel (HR 0.81; 95% CI 0.73 to 0.90; p < 0.001). The prasugrel group also had significantly lower rates of MI (7.4% for prasugrel vs. 9.7% for clopidogrel; p < 0.001), urgent target vessel revascularization (2.5% vs. 3.7%.; p < 0.001) and stent thrombosis (1.1% vs. 2.4%; p < 0.001). However, non-CABG TIMI major bleeding occurred in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (HR 1.32; 95% CI 1.03 to 1.68; p = 0.03). The prasugrel group was also noted to have significantly higher rate of life-threatening bleeding (1.4% vs. 0.9%; p = 0.01, fatal bleeding (0.4% vs. 0.1%; p = 0.002), and CABG-related TIMI major bleeding (13.4% vs. 3.2%; p < 0.001). Overall mortality did not differ significantly between treatment groups. The risk of bleeding was most prominent in patients with a prior history of transient ischemic attacks (TIA) or stroke, elderly patients (≥ 75 years) or lower-body-weight patients (< 60 kg). In patients with any one of these characteristics (n = 2,667), the incidence of non-CABG TIMI major bleeding bleeding was 4.3% with prasugrel and 3.3% with clopidogrel (p = 0.10); in patients with none of these characteristics (n = 10,804), the incidence of non- CABG TIMI major bleeding was 2.0% with prasugrel and 1.5% with clopidogrel (p = 0.17).
Thus, in patients with ACS scheduled for PCI, treatment with prasugrel at the time of the procedure was associated with significantly reduced rates of ischemic events over a median of 14.5 months, but with an increased risk of major bleeding, including fatal bleeding. Patients with a prior history of TIA or stroke, elderly patients and low-body-weight patients appeared to be at particularly high risk of bleeding.
AZD6140. AZD6140, currently in phase 3 development, is the first oral, reversible P2Y₁₂ (ADP) receptor antagonist. It is being compared to clopidogrel in ACS patients. The DISPERSE- 2 study assessed the antiplatelet effects of AZD6140 versus clopidogrel in NSTEMI-2.³³ In a substudy of the DISPERSE-2 study, patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design.³⁴ AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-hour post dose mean – 64%; AZD6140 90 mg – 79%; AZD6140 180 mg – 95%). AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel. AZD6140 is being further studied in a large-scale head-tohead phase 3 study versus clopidogrel called PLATO (A Study of Platelet Inhibition and Patient Outcomes), which will include 16,000 ACS patients.
Cangrelor. Cangrelor is a potent, selective, reversible inhibitor of ADP-induced platelet aggregation. It is being studied for ACS as an ultrafast-acting IV antithrombotic agent. The short plasma half-life of cangrelor (5 to 9 minutes) yields a rapid loss of activity following discontinuation of the infusion, which is a potentially significant safety advantage.³⁵ The initial safety and pharmacodynamics of cangrelor in patients undergoing PCI was assessed in a 2-part, phase 2I, multicenter, randomized, placebo- and activecontrolled trial.³⁵ In part 1, patients undergoing PCI were randomized to an 18- to 24-hour infusion of placebo or 1-, 2- or 4-μg/kg/minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 μg/kg/minute) or abciximab before PCI. The primary endpoint was the composite incidence of major and minor bleeding through 7 days. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% of those randomized to placebo during part 1, and in 7% receiving cangrelor compared with 10% in those randomized to abciximab during part 2, with neither of the results reaching statistical significance. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs. 5.3%, respectively; p = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 μmol/L ADP at steady state was 100% for both cangrelor 4 μg/kg/minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. A trend toward longer bleeding time prolongation and lower platelet count was observed with abciximab compared with cangrelor. This experience with IV cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y₁₂ platelet receptor with less prolongation of bleeding time then the GP IIb/IIIa receptor antagonist abciximab. The CHAMPION studies are ongoing and are comparing the safety and effectiveness of cangrelor to clopidogrel during coronary stenting.

RECENT DATA RELATING TO PHARMACO-INVASIVE THERAPY IN STEMI
The following studies provide important data that may prompt revision of the current 2004 guidelines for the management of STEMI patients treated with thrombolytic therapy.
ExTRACT-TIMI 25. The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment, Thrombolysis in Myocardial Infarction-Study 25 (ExTRACTTIMI 25) was designed to compare a strategy using enoxaparin to one using UFH in over 20,000 randomized patients with STEMI who were eligible to receive fibrinolytic therapy.³⁶ Investigators hypothesized that in STEMI patients treated with lytic therapy, the adjunctive use of enoxaparin would reduce all-cause mortality or nonfatal MI within 30 days as compared with UFH.
After initial fibrinolysis, fewer patients underwent PCI through 30 days in the enoxaparin versus the UFH group (22.8% vs. 24.2%; p = 0.027).³⁷ Among patients who underwent PCI by 30 days, the primary endpoint occurred in 10.7% of enoxaparin and 13.8% of UFH patients (p < 0.001). No differences were observed in major bleeding for enoxaparin versus UFH (1.4% vs. 1.6%). Results were similar when PCI was carried out in patients receiving blinded study drug during PCI (n = 2,178). Thus, among patients treated with fibrinolytic therapy for STEMI who underwent subsequent PCI, enoxaparin administration was associated with a reduced risk of death or recurrent MI without difference in the risk of major bleeding. The strategy of enoxaparin support for fibrinolytic therapy followed by PCI is superior to UFH and provides a seamless transition from the medical management to the interventional management phase of STEMI without the need for introducing a second anticoagulant in the cardiac catheterization laboratory.
Diabetics. In a subgroup analysis of the ExTRACT-TIMI 25, a reperfusion strategy including enoxaparin significantly improved outcomes compared with UFH among high-risk STEMI patients with diabetes mellitus undergoing fibrinolysis.38 After adjustment for the TIMI Risk Score, sex and renal function, diabetic patients were at 30% higher risk for death or MI by 30 days. Among diabetic patients, the enoxaparin strategy reduced mortality by 19% (9.5% vs. 11.8%), death/MI by 21% (13.6% vs. 17.1%), and death/MI/urgent revascularization by 19% (16.0% vs. 19.7%). The use of enoxaparin was associated with an absolute 1% increase toward higher major bleeding (2.6% vs. 1.6%). Taking efficacy and safety into account, the enoxaparin strategy offered superior net clinical benefit (death/MI/major bleed, 14.8% vs. 18.0%) compared with UFH in diabetic patients.
Women. The outcomes of cardiovascular disease differ between women and men. The safety and efficacy of pharmacological reperfusion therapy in women with STEMI was assessed in a subgroup analysis of the ExTRACT-TIMI 25 study.³⁹ Compared with men (n = 15,696), women (n = 4,783) were older and more likely to have hypertension and diabetes (p < 0.001). The unadjusted 30-day mortality rate for women was more than 2-fold higher than for men (13.2% vs. 5.4%). After adjustment for age, fibrinolytic therapy, revascularization, region, and elements of the TIMI Risk Score, women had a 1.25-fold-higher 30-day risk of death but similar risk of intracerebral hemorrhage The results showed that the 30-day rate of death or nonfatal MI in women was reduced by enoxaparin compared with UFH in women (15.4% vs. 18.3%; p = 0.007). Major bleeding was more frequent in women receiving enoxaparin compared with those receiving UFH (2.3% vs. 1.4%; p = 0.02) but similar among women and men receiving enoxaparin (2.3% vs. 2.0%; p = 0.39). The rates of death, nonfatal MI, or nonfatal major bleeding were lower with enoxaparin; absolute risk reduction was 2.6% in women (p = 0.02) and 1.6% in men (p = 0.001). Thus, in ExTRACT-TIMI 25, women presented with a profile of higher baseline risk and increased short-term mortality. In this large, contemporary clinical trial, women had similar relative and greater absolute risk reductions to men when treated with enoxaparin compared with UFH as adjunctive therapy with fibrinolysis.
Elderly. To determine the effects of age and kidney function on outcomes in patients with STEMI treated with a strategy of enoxaparin or UFH, another subanalysis of ExTRACTTIMI 25 was performed.⁴⁰ Here, a reduced dose of enoxaparin (no IV bolus and only 0.75 mg/kg subcutaneously every 12 hours) was administered to patients ³ 75 years of age, and a reduced dose in those with an estimated creatine clearance of < 30 mL/minute. The relative risk reduction (RR) with enoxaparin on the primary endpoint (death or nonfatal recurrent MI) was greater in patients < 75 years (20%) than in older patients (6%), but given the high risk of death and MI in the elderly, the absolute benefits were similar. When compared with UFH, enoxaparin was associated with a 67% increased risk of major bleeding, but the magnitude of the excess risk tended to be only 15% in patients ³ 75 years of age assigned to enoxaparin. Thus, a dose reduction of enoxaparin in the elderly may be helpful in reducing bleeding risk. A strategy of enoxaparin was superior to UFH in elderly patients with STEMI treated with fibrinolysis.
CLARITY. The Clopidogrel as Adjunctive Reperfusion Therapy- Thrombolysis in Myocardial Infarction 28 (CLARITY-TIMI 28) trial was a randomized, double-blind, placebo-controlled study of clopidogrel in 3,491 patients receiving fibrinolytic therapy for STEMI.⁴¹ The primary results of CLARITY identified a highly significant benefit of clopidogrel added to other antithrombotic agents in patients receiving lytic therapy for STEMI. A recent CLARITY subgroup analysis reports the outcomes among the 136 patients in the trial population who underwent CABG during the index hospitalization. The results showed no difference in the rates of TIMI-major or minor bleeding between the clopidogrel and placebo groups from randomization to the end of follow up (13.6% vs. 14.3%; p = 1) or from the time of CABG to the end of follow up (9.1% vs. 11.4%; p = 0.78). Among patients undergoing CABG, a trend toward a reduction in the risk of cardiovascular death, recurrent MI or recurrent ischemia requiring urgent revascularization at 30 days was observed for those taking clopidogrel (p = 0.37), consistent with the benefit seen in the overall trial population (p = 0.03). Thus, early clopidogrel treatment among CLARITY-TIMI 28 patients undergoing CABG was not associated with an increase in the rate of perioperative bleeding and showed a trend toward reduction in 30-day ischemic events.⁴²
HORIZONS AMI. The HORIZONS AMI study, presented as a late-breaking trial at the 2007 TCT in Washington D.C., showed that bivalirudin significantly reduced net adverse clinical events at 30 days — a composite of major bleeding and major adverse cardiovascular events (MACE) — as well as major bleeding alone, also 30 days out, compared with heparin plus a GP IIb/IIIa inhibitor.⁴³ More than 3,600 patients took part in HORIZONS AMI and all had STEMI with a symptom- onset < 12 hours and were randomized in a 1:1 fashion to UFH 60 U/kg IV, with subsequent boluses titrated by nomogram to an activated clotting time (ACT) of 200–250 seconds, plus a GP IIb/IIIa inhibitor (abciximab or eptifibatide), or to bivalirudin monotherapy (0.75 mg/kg bolus; infusion 1.75 mg/kg per hour), stopped at the end of the procedure, plus provisional GP IIb/IIIa inhibitors for large thrombus or refractory no-flow. In all, only 7.2% of patients in the bivalirudintreated group also received GP IIb/IIIa inhibitors in the catheterization laboratory.
For both the primary endpoints, bivalirudin was significantly better than the UFH-GP IIb/IIIa-inhibitor strategy. At 30 days, investigators saw a 40% reduction in major bleeding (p ≤ 0.0001). MACE, defined as all-cause death, reinfarction, ischemic target vessel revascularization or stroke, was no different between the two groups, however the rate of acute stent thrombosis in the first 24 hours was 4-fold higher in the bivalirudin group (1.3% vs. 0.3%) compared to the UFH-GP IIb/IIIa inhibitor group. Cardiac mortality was significantly reduced in patients in the bivalirudin arm of the study, but total mortality was not.

Antithrombotic Therapy in Patients with STEMI: Panel Recommendations
Thus, the following dosage guidelines are suggested for the use of enoxaparin in STEMI patients treated with fibrinolytics according to age/kidney function⁴⁰:
• Patients < 75 years of age
• 30 mg IV bolus followed by 1.0 mg/kg subcutaneously every 12 hours up to 8 days or hospital discharge
• Patients ≥ 75 years of age: – No IV bolus; maintenance dose 0.75 mg/kg every 12 hours • Creatine clearance < 30 mL/minute (any age): – Maintenance dose 1 mg/kg every 24 hours
• All STEMI patients receiving lytic therapy should be treated with clopidogrel 300 mg loading dose followed by 75 mg orally each day.
• Bivalirudin may be an alternative to UFH and GP IIb/IIIa in STEMI patients undergoing primary PCI.

RECENT ANALYSES RELATING TO BLEEDING DURING PHARMACO-INVASIVE THERAPY IN ACS
In patients with ACS as well as those undergoing PCI, the net clinical benefit of the myriad antithrombotic pharmacotherapies is dependent upon a balance between the benefits of reducing ischemic events and the increased risk of bleeding. Bleeding complications not only heighten patient discomfort and prolong hospital stay, but are also associated with increased morbidity and mortality independent of baseline risk factors such as increased age or impaired renal function.^44–47
Bleeding with antithrombotic therapies can be minimized. Several factors, including 1) definitions of bleeding; 2) impact of bleeding on outcomes; and 3) clinical trial evidence relating to new drugs used in the treatment of patients with ACS and undergoing PCI are reviewed below.

Definitions of bleeding. The bewildering array of major bleeding definitions in clinical trials^15,48–51 —none of which is universally accepted or employed — makes it a challenge to compare trial results (Table 3). In addition, bleeding rates of 3–5% observed in trials are much lower than those reported in clinical practice (~10%) (Figure 1).^25,52–58 Two sets of criteria — the Thrombolysis in Myocardial Infarction (TIMI)^48,59 and the Global Utilization of Streptokinase and Tissue Plasminogen Activatorfor Occluded Coronary Arteries (GUSTO) definitions⁴⁹ —are frequently used to classify severity of bleeding events among patients with ACS. The TIMI criteria are primarily laboratorybased, whereas the GUSTO system relies more on clinical criteria.
All bleeding is not the same. To be a valuable endpoint — that is, to compare antithrombotic agents to each other and across trials — a bleeding event should occur with some frequency in the population, have clinical impact and be affected by the therapy under study. Although causation is far from certain, evidence suggests that bleeding — regardless of definition — is correlated with mortality. However, some definitions may be more powerful at predicting mortality than others. Bleeding definitions that include clinical events (hemodynamic compromise, blood transfusion) invariably show a dose-response association with clinically meaningful morbidity and mortality. An analysis⁴⁵ using pooled data from 26,452 patients with ACS in multicenter, randomized trials found a stepwise increase in hazard for 30-day mortality, 30-day mortality or MI and 6-month mortality according to bleeding severity using GUSTO criteria. Among patients with procedure-related bleeding, 30-day mortality increased 1.3-fold with mild, 3.7-fold with moderate, and 16.5-fold with severe bleeding. The risk for mortality at 6 months was 2.6-fold and 10.5-fold higher among patients with moderate and severe bleeding, respectively, indicating that the implications of even so-called moderate bleeding may be more serious than intuition would suggest.
Blood transfusion has a strong relationship with clinical outcomes in patients with ACS in trials and community populations alike.^44,60 The GUSTO definition⁴⁹ includes clinical events such as transfusion; this raises the issue that transfusion may be more responsible for the prognostic implications of “GUSTO bleeding” rather than actual bleeding. Blood transfusion also has a strong relationship with clinical outcomes in patients with ACS in trials and community populations.^44,61 Adding other clinical aspects of bleeding, like hematoma, may lessen the strength of the association between bleeding and outcomes. The STEEPLE and ACUITY trials^15,51 employed broader definitions of major bleeding that were novel and not previously validated in terms of prognosis. However, the ACUITY investigators recently published an analysis showing an association between their broader definition of major bleeding and 30-day mortality.⁴⁶ Despite the breadth of this definition, rates of major bleeding remained in the 3–6% range; however, access-site bleeding and transfusion were more significant contributors to the major bleeding endpoint in the two study arms that combined antithrombin and GP IIb/IIIa inhibitor therapy compared with bivalirudin monotherapy, while more serious intracranial bleeding, reoperation for bleeding or large hemoglobin drops did not vary across treatment arms.
Broad bleeding definitions that include many data elements, clinical and otherwise, capture more events and increase rates of bleeding, thereby enhancing power to detect safety differences. Yet meaningful safety comparisons are confounded by factors that are not standardized and therefore subject to bias, as well as by the inclusions of events that vary as to their relative clinical importance and frequency in the study population.
Data from registries suggest that up to 85% of bleeding complications in patients with ischemic heart disease undergoing cardiac catheterization are related to the access site.⁶² Therefore, vascular access technique is a major modifiable risk factor for hemorrhage. Simple femoral head fluoroscopy prior to obtaining femoral arterial access can minimize vascular complications by ensuring puncture into the common femoral artery.⁶³ Alternative vascular access by utilizing the radial artery for PCI markedly reduces the risk for access site complications in both randomized comparisons against the femoral approach and in registries of “real-world” patients.^64–66 This effect appears consistent across anticoagulation strategies or patient risk.^67–69 Given these data, use of the radial artery for PCI appears to be associated with reduced bleeding risk in patients undergoing elective PCI or PCI for ACS regardless of antithrombin or antiplatelet therapies.
Lessons learned from recent ACS trials. Results from several recent, large ACS trials demonstrate differences in bleeding between strategies that may lead to assumptions of biologic superiority of one drug over another in advance of fully considering other issues associated with these trials. Observed differences in bleeding risk across treatment arms in the SYNERGY trial⁵³ have been shown to be dependent on the definition used. When TIMI criteria were applied, significantly more major bleeding was seen in the enoxaparin group, primarily due to moredecreases ≥ 5 g/dL in hemoglobin and more decreases ≥ 15% in hematocrit in patients receiving enoxaparin (15.2%) than UFH (12.5%; p < 0.001). Ironically, when the simplest, least arbitrary quantitative parameter of bleeding was used — units transfused —no difference was observed (17% vs. 16%; p = NS).
Bleeding issues were a major focus of OASIS-5,16 a doubleblind trial of 20,078 patients with ACS randomized to fondaparinux 2.5 mg or enoxaparin 1 mg/kg twice daily for 8 days or until hospital discharge. Ischemic events occurred at similar rates, but major bleeding rates were reduced in the fondaparinux group (2.2% vs. 4.1%; p < 0.001). In addition, 30-day mortality was lower among patients assigned to fondaparinux. At 6 months, the composite efficacy/safety endpoint (including ischemic outcomes plus major bleeding) was reduced (p < 0.001) in favor of fondaparinux. Thirty-day rates in the fondaparinux and enoxaparin groups were similar for patients < 65 years of age (7.4% vs. 7.5%; p = 0.883), but lower in patients ≥ 65 years of age receiving fondaparinux (12.1% vs. 15.4%; p < 0.0001), suggesting that the enoxaparin dose in elderly patients, who probably also had reduced creatine clearances, may have been excessive. Also, among patients undergoing PCI, additional UFH was used in 20.8% of the 3,118 patients in the fondaparinux group versus 55.5% of 3,089 patients receiving enoxaparin.⁷⁰
The ACUITY trial randomly assigned 13,819 patients with ACS to one of three regimens: UFH or enoxaparin plus a GP IIb/IIIa inhibitor; bivalirudin plus a GP IIb/IIIa inhibitor; or bivalirudin alone.¹⁵ When UFH plus a GP IIb/IIIa inhibitor was compared with bivalirudin alone, bivalirudin alone was associated with noninferior rates of the ischemia endpoint (7.3% vs. 7.8%; p = 0.32 [for noninferiority using a 25% boundary, the upper limit of the confidence interval reached 1.24 in ACUITY]); reduced rates of major bleeding, using the ACUITY definition (5.7% vs. 3.0%; p < 0.001); and a reduced rate of the net clinical outcome (11.7% vs. 10.1%; p = 0.02). One of the major important issues that remained undecided was that the contribution of access-site hematoma to the endpoint of major bleeding and on net clinical outcomes is not known.⁷¹ From a clinical point of view, is it acceptable to trade off an access site hematoma (a major bleeding endpoint) for an urgent invasive target vessel revascularization procedure (a major ischemic endpoint)? The question remains unanswered at this time.

Dosing as a factor in safety comparisons

Even in the context of carefully controlled clinical trials, a significant percentage of patients are dosed above recommended targets (Figure 2). Dosing was an issue in a substudy of the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, in which the incidence of major bleeding rose with increasing aspirin dosage from 81 mg to 325 mg daily in patients receiving clopidogrel or placebo, without concurrent increases in efficacy.⁵⁸ In the PROTECT-TIMI 30 trial, in 567 moderate- to high-risk NSTEMI patients treated with eptifibatide, there was a 3.2% incidence of significant bleeding.⁷² However, lack of adjustment of the maintenance eptifibatide infusion for creatine clearance ² 50 mL/minute occurred in 45% of patients and was associated with a high rate of bleeding. In fact, patients with dose-adjusted eptifibatide had no bleeding in this small study.
In pivotal trials of GP IIb/IIIa inhibitors, bleeding risk was also affected by dosage of UFH.⁷³ Currently, an ACT of 200 seconds is recommended by current guidelines.⁷⁴ The protocol for the Evaluation of Platelet IIb/IIIa Inhibition in Stenting (EPISTENT) trial⁷⁵ specified that patients receiving abciximab should receive UFH to maintain an ACT of 200 seconds; patients receiving stent plus placebo were dosed to a target ACT of 300 seconds. There was no excess bleeding; major bleeding was observed in 2.2% of stent-plus-placebo patients and 1.8% of stent-plus-abciximab patients. Similarly, in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial,⁷⁶ 2,064 patients undergoing stent implantation received eptifibatide or placebo; UFH was dosed to an ACT of 200–300 seconds. Even at this higher dosage, bleeding was observed in only 1.3% of eptifibatide patients compared with 0.4% of placebo patients (p = 0.027).
The rate of excessive dosing of UFH and GP IIb/IIIa inhibitors in community practice has been demonstrated by the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) initiative,²⁵ in which nearly half (42.0%) of the overall population with non-ST-elevation ACS received an excessive dose of at least 1 antithrombotic agent. Excessive UFH was given to 32.8%, excessive LMWH to 13.8%, and excessive GP IIb/IIIa inhibitors to 26.8% of patients who received them. Among patients > 75 years of age in this registry, 65% received an excessive dose of GP IIb/IIIa inhibitors, 40% received excessive UFH, and 20% received excessive LMWH by weight. Dosing errors were more likely in patients who were older, female, thin and who had renal insufficiency, and were independently associated with major bleeding risk.²⁶ In fact, the overall rate of major bleeding in CRUSADE — 11% — was just 6.6% among patients given 2 antithrombotic agents in correct dosages, but rose to 22.2% in patients given 2 antithrombotics both in excessive dosages. This emphasizes the importance of appropriate dosing for not just 1, but all agents,especially as patients more likely to receive excessive doses of 1 agent are more likely to receive excessive doses of others. The data summarized above suggest:

• The risk of bleeding with antithrombotic therapy is an important consideration when selecting therapy for the individual patient. Similarly, the risk of death or recurrent ischemic events must be weighed.
• The current heterogeneity of bleeding endpoints across studies limits meaningful comparisons.
• Not all components of bleeding definitions are equal in terms of impact on outcomes.
• Outcomes from recent trials may best be understood in the context of strategies of care rather than individual agents employed.
• The risk of excessive bleeding in patients who receive antithrombotic therapies is often related to a combination of patient characteristics (older age, female sex, impaired renal function) and delivery factors (dosing and stacking of anticoagulants).
• Efforts should be made in controlled clinical trials to ensure that antithrombotic regimens used in the control group represent optimal use of the conventional/control drug. Appropriate utilization may not be representative of real-world use; yet suboptimally-treated control groups do not advance clinical knowledge.
• Most importantly, readers should be critical when assessing clinical trial results and they should consider bleeding endpoints in conjunction with the ischemia reduction properties of the drugs being tested.

SUMMARY OF CATH PANEL RECOMMENDATIONS
Our goal is to improve clinical outcomes by abiding with evidence based-medicine and guidelines. A recent study by Peterson and colleagues demonstrates that adherence to guidelines is associated with improved clinical outcomes.⁵⁵ Hospitals with a higher level of adherence to guidelines have lower mortality rates.
The goals for the management of NSTE-ACS patients are rapid and accurate risk stratification, appropriate and institution- specific triage to interventional versus medical strategies and optimal pharmacologic therapy — all of which provide for a smooth and seamless transition of care between the emergency department and the cardiology service. Highrisk features or absolute treatment trigger criteria that support more aggressive medical therapy (i.e., addition of small-molecule GP IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin or other anticoagulant, and in most cases, clopidogrel) and/or that would direct clinicians toward percutaneous, mechanical/interventional strategies as the preferred modality include, but are not limited to, the presence of one or more of the following: 1) elevated cardiac markers (troponin and/or CK-MB); 2) elevated levels of inflammatory markers (particularly CRP > 3 μg/dl); 3) age > 65 years; 4) presence of ST-T-wave changes; 5) TIMI Risk Score ≥ 5; 6) diabetes; and/or 7) clinical instability in the setting of suspected NSTE-ACS.
Increased emphasis has been placed on the concept that pharmacological and interventional strategies should be riskdirected. In this vein, a hierarchical approach to ACS management in which pharmacological and mechanical modalities are pressed into service according to a sliding scale. In this model, specific clinical, electrocardiographic and/or biochemical trigger points modulate the aggressiveness of both the medical therapy and the propensity to perform early angiography with or without subsequent revascularization patients with ACS.
Although additional refinements in ACS management are still to come, evidence-based strategies suggest that prompt mechanical revascularization is associated with the best possible clinical outcomes, particularly for patients with high-risk features and in whom benefits of adjunctive pharmacoinvasive antithrombotic therapies can be consolidated. Transfer for cardiac catheterization/PCI is strongly recommended in patients who manifest high-risk features and/or aggressive treatment trigger criteria, so that this high-risk subgroup may receive definitive interventional and/or cardiology-directed specialty care at appropriate sites of care.
The importance of safe and effective anticoagulation in the spectrum of management strategies has been confirmed, and the evidence in support of enoxaparin and other antithrombotic agents has been reviewed. Dosing recommendations for enoxaparin use in the setting of PCI in NSTEMI and STEMI patients have been summarized in this consensus report. Similar recommendations have been presented for the use of oral antiplatelet agents and GP IIb/IIIa antagonists. The addition of statins, angiotensin-converting enzyme inhibitors and beta-blockers is also stressed as part of a comprehensive secondary cardioprotective strategy for patients with CAD. Most importantly, readers should be critical when assessing clinical trial results, and they should consider bleeding endpoints in conjunction with the ischemia reduction properties of the drugs being tested.

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