Review

Upstream treatment of acute coronary syndrome in the ED^?

J. Douglas Kirk MD ^a,?, Michael Kontos MD ^b, Deborah B. Diercks MD ^a

^aDepartment of Emergency Medicine, University of California, Davis, Medical Center, Sacramento, CA 95817, USA

^bCardiology Division, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA 23298, USA

Received 9 December 2009; revised 22 January 2010; accepted 23 January 2010

Abstract Rapid risk stratification, selection of downstream management options, and institution of initial pharmacotherapy are essential to ensure that patients admitted to the emergency department with acute coronary syndromes receive Optimal care. A broad range of antiplatelet and antithrombotic medications is available that permits tailoring of initial pharmacotherapy to each patient’s risk status. In the urgent setting, thienopyridines (clopidogrel and prasugrel) carry limitations including response variability and increased risk for bleeding in patients requiring subsequent Coronary artery bypass graft surgery. Glycoprotein IIb-IIIa receptor inhibitors, although they are highly effective in preventing Ischemic events, must be used with care to reduce bleeding risk. Bivalirudin, a relatively new direct thrombin inhibitor, represents another upstream option but is costly and does not have approval for this indication. Simplified institutional management paradigms can streamline the process of selecting appropriate pharmacotherapy and aid in care delivery that will optimize patient outcomes.

(C) 2011

Introduction

unstable angina and non-ST-segment myocardial infarction (NSTEMI)–the non-ST elevation acute coronary syndromes (NSTE ACSs)–are well recognized for their risk of cardiovascular morbidity and mortality, with a high combined incidence of death and myocardial infarction (MI) [1-3]. Emergency physicians play a critical role in the early management of patients with chest pain, and often, their decisions significantly affect later treatment choices and outcomes. Given the high morbidity and mortality associated with NSTE ACS as well as the complexities involved in their

^? Editorial assistance for this article was provided by Rina Kleege, MS. This assistance was funded by Schering Corp, a division of Merck and Co., Whitehouse Station, NJ.

* Corresponding author. Department of Emergency Medicine, Univer-

sity of California, Davis, Medical Center, Sacramento, CA 95817, USA. Tel.: +1 916 734 5010; fax: +1 916 734 7950.

E-mail address: [email protected] (J.D. Kirk).

care, these patients present a formidable challenge to emergency physicians.

A variety of management paradigms are available for treating patients admitted with NSTE ACS. As a result, considerable inconsistency exists among–and even within

–facilities, particularly those without established critical pathways for NSTE ACS management [1]. Compounding this problem, current guidelines provide significant latitude regarding Treatment decisions, both early, in the emergency department (ED), and later, after admission to the coronary care unit [4]. The purpose of this review was to examine current recommendations for care of patients with NSTE ACS at admission, to facilitate collaboration among members of a comprehensive care team, including emergency physicians, hospitalists, and cardiologists.

Initial stratification of risk

Patients with symptoms consistent with myocardial ischemia are heterogeneous in their risk for cardiac death

0735-6757/$ – see front matter (C) 2011 doi:10.1016/j.ajem.2010.01.023

and nonfatal ischemic events [4]. Rapid initial risk stratification is critical for reducing morbidity and mortality from ACS by shortening the time to definitive treatment and–importantly–determining downstream treatment options. In particular, estimation of risk is useful for selection of site of care (eg, coronary care unit, monitored step-down unit, or outpatient setting) and selection and timing of therapy.

Estimation of risk is a multistep process (Fig. 1) [5]. Chest pain from ischemia due to coronary artery disease (CAD) is a strong indicator of risk for a cardiac event; thus, rapid assessment of whether the patient’s signs and symptoms represent ACS is the recommended starting point for risk stratification [4]. The likelihood of ACS can be stratified into low-, intermediate-, and high-risk groups (Table 1). Patients are assessed for Short-term risk of death or nonfatal MI using history, physical findings, hemody- namic instability, electrocardiogram (ECG) findings, and biomarkers of cardiac necrosis [4]. The tempo of the clinical course should be predicated on the patient’s estimated short-term risk for cardiac events. For patients with chest discomfort or other symptoms suggestive of

NSTE ACS, a 12-lead ECG should be performed within 10 minutes of arrival and repeated serially in patients with ongoing symptoms to detect development of ST-segment elevation or depression [4,6].

Measurement of cardiac biomarkers

Current guidelines recommend measurement of cardiac biomarkers (which should include a highly sensitive and specific cardiac troponin assay) in all patients with possible myocardial ischemia [4,7,8]. In patients who present early– within 6 hours of onset of pain–measurement should be repeated 6 to 8 hours after symptom onset in patients with initially negative cardiac biomarkers. Patients who arrive at the ED more than 8 hours after symptom onset may only need a single measurement of cardiac biomarkers to rule out acute MI [4,7,8].

To accelerate diagnosis, a multimarker approach in which creatine kinase-MB (CK-MB), myoglobin, and troponin T or I (TnI) are simultaneously measured has been reported to identify positive patients earlier and provide superior risk stratification compared with a single-marker approach [9-11].

Fig. 1 Early assessment and treatment of patients with NSTE ACS. GPI, glycoprotein IIb-IIIa inhibitor; MM, medical management; NTG, nitroglycerine. Reprinted with permission from Pollack CV Jr, Braunwald E. 2007 update to the ACC/AHA guidelines for the management of patients with unstable angina and Non-ST-segment elevation myocardial infarction: implications for emergency department practice. Ann Emerg Med. 2008 May;51(5):591-606.

Feature	High likelihood of ACS Any of the following:	Intermediate likelihood of ACS Absence of high-likelihood features and presence of any of the following:	Low likelihood of ACS Absence of high-or intermediate-risk features but may have:
History Examination ECG Cardiac markers	Chest or left Arm pain or discomfort as chief symptom reproducing prior documented angina Known history of CAD, including MI Transient MR murmur, hypotension, diaphoresis, pulmonary edema, rales New, or presumably new, transient ST- segment deviation (>=1 mm) or T-wave inversion in multiple precordial leads Elevated cardiac TnI, TnT, or CK-MB	Chest or left arm pain or discomfort as chief symptoms Age N 70 y Male sex Diabetes mellitus Extracardiac vascular disease Fixed Q waves ST depression 0.5-1 mm or T-wave inversion N 1 mm Normal	Probable Ischemic symptoms in absence of intermediate-likelihood characteristics Recent cocaine use Chest discomfort reproduced by palpitation T-wave flattening or inversion b 1 mm in leads with dominant R waves Normal ECG Normal
Reprinted with permission from Anderson et al 2007, American Heart Association, Inc [4]. MR, Mitral regurgitation; TnT, troponin T.

However, these data reflect an approach that used early- generation troponin assays, which suffered from imprecision at the standard cutoff values for MI.

Table 1 Step 1 in risk stratification: determining likelihood that symptoms, signs, ECG, and cardiac biomarker findings represent ACS

Newer, high-sensitivity second- and third-generation troponin measurements have improved sensitivity, speci- ficity, and precision at lower levels. When used serially to detect changes over short periods, their sensitivity is higher than that of more traditional markers, obviating the need for CK-MB or myoglobin measurement [12]. In one study, TnI, CK-MB, and myoglobin were measured in 197 consecutive patients with chest pain and a nonischemic ECG. At a given specificity of 95%, TnI yielded the highest sensitivity of all markers at all time points. A TnI cutoff corresponding to the 10% coefficient of variation demon- strated a cumulative sensitivity of 93%, with a corresponding specificity of 81% at 2 hours; this is a significantly higher level of accuracy than that obtained with measurements of CK-MB and myoglobin, even when done a short time from symptom onset. A multimarker strategy did not provide superior overall diagnostic accuracy compared with TnI alone. More recent studies have confirmed that use of a High-sensitivity troponin assay appears to preclude the need to measure multiple markers and can identify most MIs within 3 hours of ED arrival [13,14]. However, the lower specificity for injury related to ACS, as well as recognition of the potential for Non-ACS causes of Troponin elevations, should be considered when interpreting elevations in an individual patient.

A variety of other biomarkers have been found to have independent value for predicting subsequent ischemic events, particularly mortality, in patients with ACS. However, few of these newer markers are commercially available or have been validated in an undifferentiated population, such as patients presenting to the ED. In most cases, the primary outcome event has been mortality, which is arguably less important than MI in the initial assessment of the ED patient. Currently, only 2 of these markers, B-type

natriuretic peptide (BNP) or N-terminal prohormone BNP and C-reactive protein, are available for routine use; only BNP is typically used in the ED [15]. The use of BNP was evaluated in a prospective observational substudy of patients with MI enrolled in the A to Z trial. During a 2-year follow- up, there were 230 deaths and 163 occurrences of congestive heart failure (CHF). After adjusting for age, sex, index event, renal function, hypertension, prior CHF, and diabetes, elevated levels of BNP (N80 pg/mL) were associated with an increase in subsequent death or new CHF (21% vs 7%; adjusted hazard ratio, 2.5; 95% confidence interval [CI], 2.0-

3.3) [16]. Other investigations have demonstrated similar results [17,18]. However, BNP should not be considered a specific marker of ischemia because elevations frequently occur in ED patients and are more likely to identify those who have systolic dysfunction than ACS [15,17,19].

Risk stratification models

A number of risk stratification models have been used to classify patients according to their ischemic risk at the time of presentation. At the simplest level, risk stratification can consist of measurement of a single set of biomarkers, an ECG, a history of CAD, and symptom quality. Patients with negative initial cardiac markers and a nonischemic ECG, without a history of CAD or recurrent pain, can be considered at low (approximately 0.4%) risk for MI [20]. Additional risk stratification schemes are available with varying complexity, including the Thrombolysis In Myocar- dial Infarction (TIMI), Global Registry of Acute coronary events, and Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy risk models [21-23].

All 3 scoring systems carry a class IIa recommendation in the American College of Cardiology/American Heart Hospital perform the procedure), but only the TIMI risk score is used to any degree in clinical practice [5]. This

system was derived from patients enrolled in the TIMI 11B and the Efficacy and Safety of Subcutaneous Enoxaparin in unstable angina and Non-Q-wave Coronary Events trials [21,24]. The 7 TIMI risk score predictor variables, with 1 point assigned for each, are Age 65 years or older, 3 or more risk factors for CAD, ST-segment depression on the initial ECG, 2 or more anginal events in the prior 24 hours, use of aspirin in the prior 7 days, elevated serum cardiac markers, and prior coronary stenosis 50% or greater. A history of CAD is frequently substituted for the last variable. In the TIMI 11B cohort, event rates increased from 4.7% among patients with a score of 0 or 1 to 40.9% among those with a score of 6 or 7 [21]. The TIMI risk score correlates with adverse events when applied to heterogeneous ED patients undergoing an ACS evaluation [25,26]. However, it fails to stratify patients into discrete groups according to risk score, and patients with the lowest risk as defined by a TIMI score of 0 had a 1.7% incidence of adverse events [26].

The limitations of these risk scores when applied to ED patients may be related to that most were derived from clinical trials in which patients were required to have either positive biomarkers or ECG changes for study enrollment [21,23]. Often the highest and lowest risk patients are excluded from trials, including important subgroups such as those with CHF and renal failure, 2 of the most important predictors of mortality in ACS patients. Two criteria that are frequently used–positive biomarkers and ischemic ECG findings–necessitate hospital admission regardless of other findings. Rather than applying any single risk stratification tool, recognition and identification of the high-risk variables common to most scoring systems (ischemic ECG results, abnormal levels of cardiac biomarkers, clinical variables such as Abnormal vital signs, CHF, renal failure, and age), in addition to chest pain characteristics, should be used to assess all patients.

Impact of risk and timing on treatment choices

New guidelines for the management of patients with NSTE ACS categorize approaches as “early invasive” (EIS) or “selectively invasive” (SIS) strategies and have moved toward preferential use of EIS. In EIS, patients who receive evidence-based antiischemic, antithrombotic, and antiplate- let medications undergo diagnostic angiography 4 to 24 hours after presentation, with the intent to perform revascularization. This approach is indicated in patients who have an elevated risk for clinical events (Table 2) [4].

Data suggest that efforts should be made to avoid waiting periods before intervention, particularly in high-risk patients. However, in real-world clinical practice, this is often not possible. Many patients who are admitted at night or on weekends experience prolonged delay even before receiving pharmacotherapy in anticipation of coronary angiography

Preferred Patient characteristics strategy

EIS Recurrent angina or ischemia at rest or with low-level activities despite intensive medical therapy elevated cardiac biomarkers (TnT or TnI) a New or presumably new ST-segment depression a Signs or symptoms of HF or new or worsening MR High-risk findings on noninvasive testing Hemodynamic instability sustained ventricular tachycardia PCI within 6 mo Prior CABG High-risk score (eg, TIMI, GRACE) Reduced left ventricular function (b40%) SIS Low-risk score (eg, TIMI, GRACE) Patient or physician preference in absence of high- risk features

GRACE, Global Registry of acute coronary events; HF, heart failure; MR, mitral regurgitation; TnT, troponin T. Data from Anderson et al [4]. a Key objective criteria.

and planned intervention [27]. The impact of the interval to interventional therapy has been evaluated in several trials. In the Intracoronary Stenting with Antithrombotic Regimen COOLing-off (ISAR-COOL) study, patients with ischemic symptoms plus either ST-segment depression or elevation in troponin T levels were randomly allocated to antithrombotic pretreatment for 3 to 5 days or to early intervention after pretreatment for less than 6 hours. The primary end point–a composite of 30-day incidence of large, nonfatal MI or death

Table 2 Selection of initial treatment: EIS vs SIS

–was reached in 11.6% of patients receiving prolonged pretreatment and only 5.9% of those who underwent early intervention [28]. Thus, it appears that risk is increased if the wait extends for longer durations.

Whether risk reduction requires patients to undergo coronary angiography on the day of admission compared with waiting 24 hours was examined in 2 recent trials. The Timing of Intervention in Acute Coronary Syndromes trial randomized 3031 patients with NSTE ACS to undergo either routine early coronary angiography (<=24 hours) or delayed coronary angiography (>=36 hours) [29]. Coronary angiog- raphy was performed in 98% of patients in the early- intervention group (median time, 14 hours) and in 96% in the delayed-intervention group (median time, 50 hours). At 6 months, early intervention improved the primary Composite outcome of death, MI, or stroke in the third of patients who were at highest risk (relative risk reduction, 35%) but not in the two thirds at low to intermediate risk. Another recent trial found relatively similar results [30]. Therefore, delayed intervention appears to be associated with worse outcomes only in high-risk patients.

Other data indicate that SIS, which involves invasive evaluation if optimal medical management fails or noninva- sive evaluation indicates high risk, may be as effective as EIS [31]. Success of this strategy is contingent on frequent use of

Antiplatelet therapy in early treatment “>Aspirin therapy“>noninvasive testing, with coronary angiography performed in those with high-risk findings.

Considerations guiding initial choices for antiplatelet and Antithrombotic treatment include overall risk for ischemic events as well as potential for Bleeding complications. In general, variables associated with increased ischemic risk are also associated with increased bleeding risk [32]. Choosing an acceptable balance between the two is frequently difficult, and clinicians must keep in mind that the absolute risk reduction is greatest in high-risk patients.

Antiplatelet therapy in early treatment of acute coronary syndrome

To reduce risk while waiting for definitive treatment (ie, revascularization), early, aggressive Pharmacologic therapy is warranted in most patients with NSTE ACS [4,33]. Currently, a broad range of options are available. Although these permit individualizing pharmacotherapy for each patient, the variety and combinations of therapies present a considerable challenge in selecting the best treatment to maximize ischemic benefit while minimizing bleeding risk.

Aspirin therapy

Unless it is contraindicated, aspirin should be adminis- tered to all patients with potential ACS. Current recommen- dations include an initial dose of 162 to 325 mg, followed by

81 to 162 mg daily in patients undergoing medical management, with increased doses of 162 to 325 mg in patients who have stent placement. Trial data have shown that increasing doses of aspirin are associated with a greater risk of adverse events, without obvious clinical benefit [34,35]. In an effort to better define the optimal dose of oral Antiplatelet agents, the clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial compared, in 2 x 2 fashion, clinical outcomes of low (75-100 mg) and high (300-325 mg) aspirin dosages in combination with clopidogrel in a standard (300-mg load followed by 75 mg/d for 30 days) or high (600-mg load followed by 150 mg/d on days 2-7, then 75 mg/d until day

30) dosage in ACS patients [35]. Results showed no difference in clinical events or bleeding with high-vs low- dose aspirin.

Clopidogrel

The efficacy of clopidogrel, one of the most widely used antiplatelet agents, has been demonstrated in a broad range of patient populations across a wide range of settings [33,36-38]. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial randomly allocated more than 12 000 patients with NSTE ACS (defined as positive

biomarkers or ischemic ECG changes) presenting within 24 hours of the onset of symptoms to either placebo or clopidogrel (300-mg loading dose followed by 75 mg/d) in addition to aspirin [33]. In this study, the risk for the Composite end point—Cardiovascular death, MI, or stroke

–was reduced 20% with clopidogrel. Notably, a statisti- cally significant benefit associated with clopidogrel admin- istration was observed within the first few hours of treatment. In the subset undergoing percutaneous coronary intervention (PCI), pretreatment with clopidogrel and aspirin followed by long-term therapy was associated with a significantly lower rate of the composite of cardiovascular death, MI, or any revascularization, starting as early as 2 days after PCI and continuing through 30 days. These data reinforce the importance of early, aggressive pharmacologic therapy in this patient population.

As would be expected, the additional antiplatelet effects of clopidogrel, while reducing risk for ischemic events, are also associated with increased risk of bleeding. The risk can be reduced by decreasing the dose of concomitant aspirin. In a retrospective analysis of the CURE trial, use of clopidogrel in combination with low-dose (b100 mg) aspirin was associated with a significantly lower risk of major bleeding compared with high-dose (N300 mg) aspirin alone (2.6% vs 4.0%) [39].

Dosing and timing of clopidogrel administration remain matters of some controversy. Current guidelines recommend the standard 300-mg dose in the acute setting but state that preloading with a 600-mg dose is acceptable [4]. Data from the ISAR: Choose between 3 High Oral doses for Immediate clopidogrel Effect (ISAR-CHOICE) study indicate that a 600-mg loading dose is associated with greater inhibition of platelet aggregation but not with an improvement in clinical outcomes. Higher doses (eg, 900 mg) were not associated with additional significant suppression of Platelet function, possibly as a result of plateauing of clopidogrel absorption [40]. Although use of a higher loading dose of clopidogrel can overcome some of the wide response variability associated with the 300-mg dose, substantial response variability remains [41,42]. The alternative dosing regimen of a double bolus of 300 mg of clopidogrel overcomes, at least in part, limited clopidogrel absorption and is associated with greater platelet inhibition than conventional loading doses [43].

Although increasing the dose of clopidogrel reduces clinical events, variations in the enzyme CYP2C19, which is responsible for converting the prodrug to its active form, are an important source of clopidogrel resistance. Polymor- phism, which is present in 30% to 55% of patients [44], results in a substantially reduced response and worse outcomes [45]. This reduced response appears relatively unaffected by increased clopidogrel dosing [46].

As described, in the CURRENT-OASIS 7 trial, there was no overall difference when clopidogrel was given in a standard or high dose in ACS patients [34]. However, in the subset of patients who underwent PCI, the risk of the

combination of cardiovascular death, MI, and stroke was significantly lower (15% relative reduction) in the high- dose group, as was the risk of Stent thrombosis. Increased dose clopidogrel was not associated with an increase in bleeding.

In clinical practice, clopidogrel may be withheld from patients whose coronary anatomy is unknown, based on increased risk for serious bleeding among patients who receive clopidogrel within 5 to 7 days of undergoing Coronary artery bypass grafting (CABG) [47,48]. Although this presents a considerable challenge when considering upstream use of clopidogrel, less than 10% of patients enrolled in ACS trials undergo CABG, and the likelihood of emergent CABG is substantially lower [49]. Unfortu- nately, attempts to determine whether a patient will subsequently require CABG at the time of admission have been largely unsuccessful [50]. Therefore, the benefit that clopidogrel offers to most treated patients must be weighed against the small downstream risk of bleeding in patients undergoing CABG.

Prasugrel

Prasugrel, a new thienopyridine, has been observed to have greater potency and a faster onset of action compared with clopidogrel [51]. The TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial Infarction (TRI- TON-TIMI) 38 study compared prasugrel (60-mg loading dose; 10-mg daily maintenance dose) with clopidogrel (300- mg loading dose; 75-mg daily maintenance dose) in 13 608 patients with moderate- to high-risk NSTE ACS undergoing scheduled PCI [52]. The primary efficacy end point (a composite of cardiovascular mortality, nonfatal MI, or nonfatal stroke) was reduced 19% (P b .001) among patients who received prasugrel compared with those who received clopidogrel. Importantly, a significant proportion of the risk reduction with prasugrel occurred during the first 3 days of the trial (Fig. 2) [52], suggesting that suppression of platelet hyperreactivity early after PCI is critical for reducing downstream risk. In addition to the short-term benefit, a significant reduction in risk was also seen in events occurring from 30 to 365 days after enrollment [53]. One limitation of the trial design was that the loading dose of clopidogrel (300 mg) was lower than what is typically recommended [4], and it was given after angiography was performed rather than early, at the time of admission.

The increased efficacy of prasugrel was counterbalanced by a clinically significant increased risk of bleeding, particularly in patients who were older than 75 years, had prior Cerebrovascular events, or weighed less than 60 kg

[52]; current recommendations suggest that prasugrel should not be used in these patients. Furthermore, a substantial increased rate of bleeding related to CABG was also seen. Although prasugrel represents an incremental evolution in antiplatelet therapy, the risks and benefits

attendant upon its use must be carefully weighed. Currently, prasugrel is only indicated for patients under- going PCI. Future studies will address treatment in medically managed patients who do not undergo revascu- larization. Studies are also needed to evaluate prasugrel in the catheterization laboratory vs early upstream adminis- tration of clopidogrel. These studies will need to be completed before revising current antiplatelet strategies in the ED.

Glycoprotein IIb-IIIa receptor inhibitors

The glycoprotein (GP) IIb-IIIa receptor inhibitors abciximab, eptifibatide, and tirofiban have long been mainstays of antiplatelet therapy. As intravenously admin- istered agents, they do not share the limitations of clopidogrel in time to maximum effect; moreover, these agents block the final common pathway of platelet aggregation by occupying the GP IIb-IIIa receptor and blocking its affinity for fibrinogen, resulting in more than 90% inhibition of platelet aggregation [54].

How to best integrate these agents with oral antiplatelet agents remains an evolving subject. Current guidelines indicate that eptifibatide and tirofiban, with (class IIa, Level of evidence B [limited population risk strata evaluated]) or without (class I [should be administered], level of evidence B) clopidogrel, may be administered to patients in whom EIS is selected. Their use in patients in whom an initial conservative strategy is selected (class IIb [may be considered], level of evidence B) is less convincing. Abciximab is contraindicated for upstream use in the ED [4].

• • 1. Timing of administration

Timing of the administration of these agents is also a matter of controversy. Currently, GP IIb-IIIa receptor inhibitors are typically initiated in the cardiac catheterization laboratory, where interventional cardiologists can maintain control over the balance between ischemic benefit and bleeding risk. However, this delay can potentially result in ischemic events in some high-risk patients. An early meta- analysis indicated benefit when GP IIb-IIIa inhibitors were administered upstream, with a 34% relative reduction in risk vs placebo for the composite of death or nonfatal MI before PCI (2.5% vs 3.8%, respectively) and a 41% reduction for PCI-related events (4.9% vs 8.0%) [55]. In addition, upstream GP IIb-IIIa inhibitors were associated with a 50% reduction in risk of all-cause mortality and a 35% reduction in the risk of procedure-related mortality. Observational data from the CRUSADE registry as well as the National Registry of Myocardial Infarction-4 also found a significant reduction in mortality with early (before coronary angiography) treatment in non-ST-segment myocardial infarction patients [27,56].

In contrast, a recently completed trial, performed in the era of upstream clopidogrel use, demonstrated less benefit

Fig. 2 Key end points in TRITON-TIMI 38. Panel A shows data for the primary efficacy end point and for the key safety end point (TIMI major bleeding not related to CABG) during the full follow-up period. The hazard ratio for prasugrel, as compared with clopidogrel, for the primary efficacy end point at 30 days was 0.77 (95% CI, 0.67-0.88; P b .001) and at 90 days was 0.80 (95% CI, 0.71-0.90; P b .001). Data for the primary efficacy end point are also shown from the time of randomization to day 3 (panel B) and from 3 days to 15 months (panel C). In panel C, the number at risk includes all patients who were alive (regardless of whether a nonfatal event had occurred during the first 3 days after randomization) and had not withdrawn consent for follow-up. The P values in panel A for the primary efficacy end point were calculated with the Gehan-Wilcoxon test; all other P values were calculated with the log-rank test. TRITON TIMI-38, TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel–Thrombolysis In Myocardial Infarction 38. Reprinted with permission from Wiviott 2007, Copyright 2007 Massachusetts Medical Society. All rights reserved [52].

with upstream GP IIb-IIIa antagonist use. The randomized, double-blind, EARLY glycoprotein IIb-IIIa inhibition in non-ST-segment elevation Acute Coronary Syndrome (EARLY ACS) trial, designed to reflect real-world practice, evaluated the use of early, front-loaded GP IIb-IIIa inhibitors vs delayed provisional use in the catheterization laboratory in 9492 patients with NSTE ACS in whom an invasive approach was planned (but not earlier than the day after admission) (Fig. 3) [57]. The primary end point (a composite of death, MI, and recurrent ischemia requiring urgent revascularization or thrombotic bailout use of eptifibatide

during PCI) was not significantly different in the early vs delayed treatment groups at 30 days (9.3% vs 10.0%, respectively). Early treatment was associated with a significant increase in bleeding, however.

• • 1. Troponin status

A number of trials have demonstrated that the efficacy of GP IIb-IIIa receptor inhibitors is dependent on troponin status, as patients with positive troponins appear to benefit preferentially from these agents [57-60]. Therefore, based on the somewhat contradictory data for upstream therapy with

Fig. 3 Primary end point events in EARLY ACS during medical therapy and after PCI or CABG. Kaplan-Meier estimates of rates of the primary efficacy end point are shown for patients who received medical therapy alone, who underwent PCI, and who underwent CABG. Data on interventional strategies were missing for 8 patients (4 in each study group). One death in the delayed-eptifibatide group that occurred 16 days after randomization was not included because of missing data regarding use of revascularization. Patients who underwent both CABG and PCI (n = 47) were categorized according to procedure performed first. In the table below the flow chart, all events that occurred before PCI or CABG are included in the total number of events that occurred during medical therapy. All events shown are the first occurrence of the primary end point. The summaries are shown as the total number of events, along with the number at risk and Kaplan-Meier rate estimates. For event rates after revascularizations, events were counted after procedures were actually performed. EARLY ACS, EARLY glycoprotein IIb-IIIa inhibition in non-ST-segment elevation Acute Coronary Syndrome. Adapted with permission from Giugliano 2009, Copyright 2007 Massachusetts Medical Society. All rights reserved [57].

GP IIb-IIIa receptor inhibitors, their use in the ED should be reserved for high-risk patients, such as those with Troponin elevations, who have a low risk of bleeding (younger, absence of renal insufficiency).

• • 1. Dosing considerations

Another important consideration for treatment with GP IIb-IIIa receptor inhibitors is the role of dosing. The risk of bleeding with these medications was demonstrated in patients from the CRUSADE registry, in which 42% of patients with NSTE ACS who received antithrombotic agents received at least 1 initial dose outside the recommended range [61]. Factors associated with excess dosing included older age as well as female sex, renal insufficiency, low body weight, diabetes mellitus, and CHF. Relative to those patients not administered excess dosages, patients with excess dosages of GP IIb-IIIa inhibitors had higher risks for major bleeding (adjusted odds ratio, 1.36; 95% CI, 1.10-1.68).

Anticoagulant therapy in early treatment of ACS

As with antiplatelet agents, current guidelines link the use of recommended anticoagulant therapies to specific man- agement strategies, reflecting evidence that pharmacotherapy can be tailored to optimize the benefit and minimize the risk in individual patients. Among patients undergoing invasive management, class I, level of evidence A recommendations include enoxaparin and unfractionated heparin (UFH); both bivalirudin and fondaparinux carry class I, level of evidence B recommendations [4]. Among those in whom SIS is chosen, enoxaparin, UFH (class I, level of evidence A) or fondaparinux (class I, level of evidence B) is recommended. In these conservatively managed patients, enoxaparin or fondaparinux is preferable to UFH, and fondaparinux is preferable if patients are at increased bleeding risk. It is also noteworthy that among patients undergoing SIS, either enoxaparin or fondaparinux is preferred over UFH unless

CABG is anticipated within 24 hours. The recent 2007 ACC/ AHA recommendations incorporate use of a reduced, weight-based dose of UFH. This includes a bolus of 60 U/ kg with a maximum dose of 4000 U, and an initial infusion of 12 U/kg per hour, initiated at no greater than 1000 U/kg per hour. This recommendation is based on observational data from randomized controlled trials in STEMI indicating that patients with higher partial thromboplastin time tend to have worse overall outcomes [62,63]. Interestingly, these out- comes do not appear entirely related to increased bleeding complications but were associated with increased ischemic events. Patients being treated with enoxaparin should be given 1 mg/kg subcutaneously every 12 hours. At the time of PCI, those patients who received their last dose less than 8 hours before the procedure need no additional dosing; those whose last dose was more than 8 hours may receive an additional bolus of enoxaparin 0.3 mg/kg intravenously. In patients with significant renal dysfunction (creatinine clearance, b30 mL/min), the dose is reduced to 1 mg/kg every 24 hours. As an alternative, UFH is frequently used in patients with significant renal dysfunction, particularly those who are likely to undergo PCI.

The Acute Catheterization and urgent intervention Triage strategY Timing study randomly assigned 13 819 patients to heparin plus a GP IIb-IIIa inhibitor, the direct thrombin inhibitor bivalirudin plus a GP IIb-IIIa inhibitor, or bivalirudin alone [64]. Bivalirudin alone and heparin plus a GP IIb-IIIa receptor inhibitor had similar rates of the ischemic end point (7.8% vs 7.3%, respectively; P = .32), but bivalirudin was associated with significantly reduced rates of major bleeding (3.0% vs 5.7%; P b .001) and of the net clinical outcome (10.1% vs 11.7%; P = .02). It should be noted, however, that the net clinical outcome included bleeding, which in turn incorporated access-site hematoma in its definition. Removing this clinically minor end point might have significantly affected the relative rates of the net clinical outcome [64].

A second randomization compared patients who received upstream or catheterization laboratory administration of GP IIb-IIIa inhibitors. The primary composite end point (death from any cause, MI, or unplanned revascularization for ischemia) occurred in 7.9% of patients who received deferred treatment and 7.1% of those who received routine Upstream administration (P = .13). Potential explanations for this limited benefit (which did not meet the noninferiority criterion) among patients in the “delayed” group are that GP IIb-IIIa receptor inhibitors were initiated an average of only 3.9 hours later than in the upstream group and that the population included in this study was at relatively lower risk compared with other ACS trials that enrolled patients at high risk [65].

An important limitation of bivalirudin for upstream use is its overall cost. Although bivalirudin is relatively inexpen- sive when used in the catheterization laboratory, with more prolonged infusions, such as would be required for upstream treatment initiated in the ED, cost could exceed that of other

treatments (combinations of a heparin and GP IIb-IIIa inhibitor) on a per-day basis. In addition, bivalirudin is not approved by the FDA for initiation in the ED. It remains to be seen whether this drug will eventually be approved for upstream use.

Conclusions

A wide variety of therapeutic options are available for initial care of the patient admitted with ACS. Although this variety permits tailoring of pharmacotherapy to the individ- ual patient, it also imposes a considerable burden on health care professionals responsible for upstream care. The complexity of considerations to optimize early care for these patients is further increased by ever-emerging trial data and updated guidelines that must be incorporated into institutional care paradigms and critical pathways. In addition, physicians face pressures from national health care standards organizations, whose requirements for providing “quality care” can be inconsistent with the most recent evidence and guidelines. Together, these factors contribute to considerable inter- and even intrainstitutional variability in patient care.

With the understanding that care administered in the ED has a profound impact on later treatment choices and patient outcomes, the shift toward a preferred EIS suggests that new collaborative pathways must be generated, integrating care provided by emergency physicians, hospitalists, and cardiol- ogists. Simplified institutional management pathways may relieve the considerable burden of selecting appropriate pharmacotherapy and ensuring that the initial management of patients is optimized.

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