Article, Cardiology

ED to catheterization laboratory: a roundtable integrating trials with practice

Unlabelled imageAmerican Journal of Emergency Medicine (2011) 29, 1203-1216

Review

ED to catheterization laboratory: a roundtable integrating trials with practice

Charles V. Pollack Jr MD a,b,?, Gerard X. Brogan Jr MD c,d, Marc Cohen MD e,f, Deborah Diercks MD g, Cindy Grines MD h, Timothy D. Henry MD i,

Neal S. Kleiman MD j,k, Robert P. Giugliano MD, SM l,m

aUniversity of Pennsylvania School of Medicine, USA

bPennsylvania Hospital, Philadelphia, USA

cForest Hills Hospital, USA

dNYU School of Medicine, New York, NY, USA

eDivision of Cardiology, Newark Beth Israel Medical Center, Newark, NJ, USA

fMount Sinai School of Medicine, New York, NY, USA

gUniversity of California Davis Medical Center, Sacramento, USA

hCardiology, Academic Affairs, William Beaumont Hospital, Royal Oak, MI, USA

iMinneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, MN, USA jcardiac catheterization laboratory, Methodist DeBakey Heart & Vascular Center, Houston, TX, USA kWeill Medical College of Cornell University, New York, NY, USA

lCardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA

mHarvard Medical School, Cambridge, MA, USA

Received 12 June 2010; revised 24 July 2010; accepted 11 August 2010

Abstract

Background: Clinical trials are the foundation underlying clinical decision-making. However, stringent inclusion and exclusion criteria may reduce the generalizability of their results, especially for patients seen in the emergency department (ED). Guideline recommendations, based on clinical trials and pertinent registries, apply to broad populations, but not all patients cared for at the bedside fit the predefined categories that make guidelines practical. Furthermore, these documents may not incorporate the latest evidence. As a result, other factors (eg, individual patient characteristics, clinician experience, cost, regulatory labels, expert opinions) often result in clinical decision-making that varies from strict adherence to guideline recommendations.

Objectives: These challenges demonstrate a need to integrate clinical data and guidelines advice with actual ED practice in a manner that will be consistent with decisions made later in the continuum of care. Discussion: In recognition of these issues, a roundtable was convened in New York City on June 5, 2009, to discuss the implications of recent trials involving patients with Non-ST-segment elevation acute coronary syndromes. Eight physicians, representing both emergency medicine and cardiology, shared information on advances and clinical trial results in antiplatelet treatment, guidelines, and other

* Corresponding author. Emergency Medicine, Pennsylvania Hospital, University of Pennsylvania, 800 Spruce Street, Philadelphia, PA 19104, USA. Tel.: +1 215 662 6311.

E-mail address: [email protected] (C.V. Pollack).

0735-6757/$ – see front matter (C) 2011 doi:10.1016/j.ajem.2010.08.008

developments in patient care. This article is based on transcripts of their presentations and the ensuing discussions that were of particular importance for emergency physicians.

Conclusions: Although guidelines and clinical registries can provide broad direction for practice, there is no substitute for a prospective, multidisciplinary, institution-specific, consistent, evidence-based approach to patient management.

(C) 2011

Introduction

Randomized, controlled, blinded clinical trials are widely accepted as the gold standard underlying guideline recom- mendations and treatment decisions made in real-world clinical practice. However, although clinical trials provide substantial information to generate evidence-based guideline recommendations regarding care of broad patient popula- tions, numerous other considerations affect treatment decisions, including results of trials published after the latest iteration of guidelines, individual patient factors, clinician experience, cost, regulatory labels, and expert opinion. Moreover, clinical trials of patients with non-ST-segment elevation (NSTE) acute coronary syndromes and those undergoing percutaneous coronary intervention (PCI) typically have stringent inclusion and exclusion criteria; thus, many patients will not fit precisely into the defined categorizations that are required to generate practical guide- lines. For example, certain strategies, such as use of warfarin after myocardial infarction (MI) and genotyping to identify optimal warfarin or maintenance clopidogrel dosing, have not been adopted in the United States despite evidence from randomized, Controlled clinical trials showing that these strategies confer considerable patient benefit [1-4]. In addition, physicians often use combination regimens in their practice that have not been specifically studied in clinical trials. These facts suggest that scientific evidence derived from randomized clinical trials is not the only driver of clinical practice.

An abundance of recent clinical evidence directly impacts the assessment and treatment of patients with NSTE ACS in Contemporary practice. The latest iterations of both the American College of Cardiology/American Heart Association (ACC/AHA) and the European Society of Cardiology guidelines incorporate some, but not all, of this evidence into treatment recommendations, thus leaving considerable room not only to interpret established clinical data and guidelines but also to identify additional key data that may influence care paradigms, especially in relation to treatment in the emergency department (ED) [5-7]. For these reasons, a roundtable was convened on June 5, 2009, in New York City, to discuss the implications of recent trials on clinical practice.

Eight physicians, representing both emergency medicine and cardiology, shared information and their experience in antiplatelet and antithrombotic treatment, clinical trial results, interpretation of guidelines, and other issues related

to patient care. The physicians were selected for their expertise and prominence, and to obtain an appropriate balance between the 2 disciplines. Selecting physicians from geographically disparate locales helped facilitate the consid- eration of Regional variations in care. Each author was responsible for drafting and editing his or her respective section, and all participants provided subsequent critical review and commentary for this article. AdelphiEden Health Communications, New York, NY, provided logistical and editorial support, funded by Schering Corporation (now Merck & Co.), which had no role in the discussions, interpretation of data, or writing of this report.

This article, based on the transcripts of presentations and discussions held at that roundtable meeting (Acute Coronary Syndromes: From the Emergency Department to the Catheterization Laboratory–Integrating Evidence from Recent ACS/NSTEMI Trials into Clinical Practice), reports both the evidence summarized by and the opinions of the participants. (Where applicable, we include classes and levels of evidence for treatment effects, based on the ACC/ AHA recommendations [8].) It is noteworthy that even in today’s environment, with considerable data available to support treatment decisions, important differences remain regarding optimum care paradigms in the ED for this challenging patient population [7]. We therefore focus on issues of particular importance for the practice of emergency medicine. A companion article, published elsewhere, focuses on the implications of these data for cardiologists [9]. Together, these articles comprise a complete report of the presentations and discussions held at the roundtable meeting.

Integrating recent antiplatelet/antithrombotic treatment advances into clinical practice: 2008 to 2009

Presenter: Neal Kleiman, MD

Director, Cardiac Catheterization Laboratory, Methodist DeBakey Heart & Vascular Center, Houston, Tex; Professor of Medicine, Weill Medical College of Cornell University, New York, NY.

A number of recent antiplatelet therapy advances have potential to change the treatment landscape.

  • P2Y12 receptor antagonists. First and foremost, a new thienopyridine agent–prasugrel–has been approved (July 2009) by the Food and Drug Administration. The pivotal prasugrel investigation–TRITON-TIMI 38–ran- domly assigned 13 608 patients with moderate- to high-risk

Table 1 Trial acronyms

ACUITY: Acute Catheterization and urgent intervention Triage strategY

CAPTURE: c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina

CLEAR PLATELETS: Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets

CREDO: Clopidogrel for the Reduction of Events During Observation

CRUSADE: Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC and AHA Guidelines

CURRENT-OASIS 7: Clopidogrel optimal loading dose Usage to Reduce Recurrent EveNTs-Organization to Assess Strategies in Ischemic Syndromes

CURE: Clopidogrel in Unstable Angina to Prevent Recurrent Events

EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Non-ST- Segment Elevation Acute Coronary Syndromes

ESPRIT: Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy

GUSTO IV ACS: Global Utilization of STrategies to Open occluded arteries IV in Acute Coronary Syndromes

HORIZONS-AMI: Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction

INTERACT: Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment

OASIS-5: Fifth Organization to Assess Strategies in Acute Ischemic Syndromes

PARAGON-B: Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network

PRISM-PLUS: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms

PURSUIT: Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy

TRITON-TIMI 38: Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel- Thrombolysis in Myocardial Infarction

ACS undergoing scheduled PCI to receive either prasugrel (60-mg loading, 10-mg daily dose) or clopidogrel (300-mg loading, 75-mg daily dose) (Table 1) [10]. Although patients with ST-segment-elevation MI (STEMI) undergoing Primary PCI could receive clopidogrel or prasugrel in the ED before angiography, this applied to only 18% of the patients enrolled in the trial. The remaining 82% (or 10 074 patients) with NSTE ACS, in whom coronary anatomy was known to be suitable for PCI before randomization, received prasugrel or clopidogrel after angiography. The primary end point–a composite of death from Cardiovascular causes, nonfatal MI, or nonfatal stroke–occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel, translating to a 19% relative risk reduction for these end points. Similarly, in the prasugrel group, there were significant reductions for MI (9.7% vs 7.4%), urgent

target-vessel revascularization (3.7% vs 2.5%), and Stent thrombosis (2.4% vs 1.1%). Notably, the improved efficacy seen with prasugrel came at the cost of significantly increased bleeding (2.4% in the prasugrel group vs 1.8% in the placebo group; P = .03). Importantly, fatal thrombolysis in MI (TIMI) major bleeding occurred in significantly more patients treated with prasugrel (0.4%) than in those treated with clopidogrel (0.1%) (P = .002). This phenomenon, in which increased antithrombotic efficacy is accompanied by increased bleeding, has been observed in numerous trials of antiplatelet and anticoagulant medications [11-13]. The site of bleeding is particularly important because some bleeding events (eg, intracranial hemorrhages) are associated with high rates of mortality, whereas bleeding at other sites is rarely fatal [14].

Questions remain regarding how prasugrel will be used clinically in the broader setting as well. It is clear from existing data that the drug will be useful in treating patients with STEMI undergoing primary stenting; untested areas in which prasugrel may be useful include high-risk non-ACS PCI (eg, patients with multiple stents, small vessels, or poor ventricles) and short-duration use in high-risk patients [15]. In addition, there are no data regarding the efficacy of this agent in the undifferentiated ACS patients treated early in the ED setting; neither are there data on the consistency of accurate recognition of ACS patients at high risk for bleeding (those with a history of transient ischemic attack/stroke, who are elderly, and/or with low body weight) if treated with prasugrel in the ED.

A second novel strategy involves tailoring therapy based on measured or predicted individual patient response to clopidogrel. Recent data suggest that the vasodilator- stimulated phosphoprotein index, a marker of P2Y12 reactivity measured using flow cytometry, may be useful for determining risk of stent thrombosis [16]. In one study, clopidogrel dosing guided by vasodilator-stimulated phos- phoprotein index was associated with a significantly lower rate of stent thrombosis and major adverse cardiovascular events and did not have a significant effect on bleeding. Other recent advances include Cytochrome P450 2C19 genotyping to identify patients who are less likely to benefit from clopidogrel (and, conversely, those who might benefit from prasugrel) [16,17].

The primary antiplatelet activity of thienopyridines is exerted in the prevention of platelet activation; emergency physicians also may use anti-aggregation antiplatelet therapy in the management of ACS. Recent data– particularly from the EARLY ACS trial–provide informa- tion on the use of glycoprotein (GP) IIb/IIIa inhibitors, which inhibit aggregation of activated platelets in clinical practice (discussed in detail later) [18]. EARLY ACS was modeled on the PURSUIT trial, which demonstrated a 1.5% absolute reduction in the incidence of the primary end point of death or nonfatal MI at 30 days among patients (n = 10,948) who received GP IIb/IIIa inhibitors compared with placebo [19].

When evaluating the EARLY ACS trial, 2 key questions remain: How does one integrate results from the EARLY ACS trial with results from earlier studies, including–but not limited to–the PURSUIT trial? Should physicians view the EARLY ACS trial as part of a larger continuum of evidence or as an isolated, but contemporary, single trial?

The EARLY ACS trial: top-line results and implications

Presenter: Robert P. Giugliano, MD

Associate Physician, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Mass; Associate Professor in Medicine, Harvard Medical School, Boston, Mass.

EARLY ACS was designed jointly by emergency medicine physicians and cardiologists to address an unanswered question in the early management of patients with NSTE-ACS. Since the 2002 ACC/AHA update to the guidelines for management of unstable angina and NSTEMI (in use at the time of the trial design) stated that intravenous GP IIb/IIIa inhibitors could be administered either upstream (before angiography) or downstream (after angiography) in patients with moderate- to high-risk NSTE ACS who were being managed with an Early invasive strategy, controversy has existed regarding the optimal timing of their administration (Table 2) [20]. Considerable variability was seen in the early use of GP IIb/IIIa inhibitors, with some emergency physicians routinely administering GP IIb/IIIa inhibitors early, others rarely starting GP IIb/IIIa inhibitors in the ED, and many awaiting consultation with the on-call interventionalist [21,22]. One prior trial randomly assigned patients to upstream vs downstream GP IIb/IIIa inhibition; however, the very short difference in duration of GP IIb/IIIa inhibitor therapy before PCI (on average, approximately 4 hours) did not provide a sufficient opportunity to truly test the upstream hypothesis [23]. This is particularly relevant in the roughly 50% of hospitals in the United States where the time to angiography is 21 hours or longer after presentation [24].

Table 2 Recommendations for management of patients with UA/NSTEMI, ACC/AHA guidelines, 2002 [19]

Class I (level of A platelet GP IIb/IIIa antagonist should be evidence: A) administered, in addition to aspirin and

heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI.

Class IIa (level of A platelet GP IIb/IIIa antagonist should be evidence: B) administered to patients already receiving

aspirin, heparin, and clopidogrel in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administered just prior to PCI.

Data from J Am Coll Cardiol. 2002;40:1366-1374.

A total of 9492 patients with high-risk NSTE ACS (defined as either [1] at least 2 of the following: elevated troponin or creatine kinase-myoglobin B [CK-MB] level, ST-segment deviation, age >=60; or [2] age 50-59 years, a history of cardiovascular disease, and an elevated cardiac biomarker level) in whom an angiogram was planned in the next 12 to 96 hours were randomized in EARLY ACS (Fig. 1) [18]. Importantly, the study only enrolled patients who could begin study treatment within 12 hours of presentation to the first ED, thus ensuring a high-risk cohort in which early, aggressive therapy should be of most benefit. This was determined to be a reasonable cutoff for “early” treatment based on data from trials and registries. The primary end point was the 4-way composite of death, MI, recurrent ischemia requiring urgent revascularization, or thrombotic bailout (a thrombotic complication during PCI that required use of a GP IIb/IIIa inhibitor) at 96 hours. The key secondary end point was the composite of death or MI through 30 days, while the major safety end points included bleeding and transfusions through 120 hours.

Physicians selected the adjunctive antithrombotic agent

(most commonly either enoxaparin or unfractionated hepa- rin, with a small minority of patients receiving bivalirudin or fondaparinux), which was adjusted for weight and renal function. All patients received aspirin. clopidogrel use was encouraged according to practice guidelines (class I, Level of evidence [LOE] A), although physicians had to declare at the time of randomization whether they intended to administer it early or defer the decision until after angiography [5].

Two important factors bear on the interpretation of the EARLY ACS data with regard to use of eptifibatide peri- PCI. First, as emergency physicians know well, it is difficult to predict, based on their initial presentation, which patients will eventually undergo PCI; ultimately, the decision whether a patient would undergo PCI was made after the angiogram was performed. Although the primary intent was to enroll patients with high-risk NSTE ACS, most of whom

Fig. 1 Study design of the EARLY ACS trial [17]. CVD, cardiovascular disease; SAEs, serious adverse events; TnT/I = troponin T or I. Data from N Engl J Med. 2009;360:2176-90.

would undergo PCI, 41% of the patients in this trial did not undergo PCI after the initial angiogram (13% underwent coronary artery bypass graft [CABG] and 28% were medically managed without a revascularization procedure) [18]. Second, because treatment guidelines recommend GP IIb/IIIa inhibition in high-risk patients undergoing PCI (class I, LOE A), the protocol permitted physicians (at their discretion) to request use of a blinded “PCI kit” to ensure that patients received eptifibatide during PCI [5,6,25,26]. Sur- prisingly, physicians called for the PCI kit for only 26% of patients who underwent PCI. Thus, 74% of patients who were randomly assigned to upstream placebo with deferred GP IIb/IIIa inhibition did not have eptifibatide running at the time PCI commenced.

The patients enrolled were at high risk (average age, 68 years; 32% women; 30% with diabetes; 28% with a history of MI); 84% had positive troponins, but only a third were enrolled within 4 hours of presentation. The initial therapies were aggressive and consistent with current guidelines, with the vast majority receiving aspirin (97%) (class I, LOE A), ?- blockers (88%) (class I, LOE B), statins (87%), angiotensin- converting enzyme inhibitors/angiotensin receptor blockers (78%) (class I, LOE A for appropriate patients), and early clopidogrel (75%) (class I, LOE A) [5]. Median time to coronary angiography was 21.4 hours.

The primary 4-way Composite end point at 96 hours occurred in 9.3% of those randomly assigned to early, routine eptifibatide compared with 10.0% of those assigned to delayed, provisional eptifibatide (P = .23), with no difference observed in any of the individual components or other composites at 96 hours (Table 3). There was a trend toward fewer deaths or MIs through 30 days with early, routine eptifibatide (11.2% vs 12.3%, P = .08), and similar favorable trends in other composite end points at 30 days. Patients with diabetes, with positive baseline troponin levels, and less than 75 years of age tended to have a more favorable outcome with early routine eptifibatide, although none of the statistical interaction tests was significant. Most relevant to emergency physicians, patients who were enrolled within 4 hours of arrival had primary event rates of 8.9% vs 10.5%, and 30-day rates of death or MI of 11.1% vs 12.8% for early routine vs delayed, provisional eptifibatide (P = not significant). Meanwhile, the rates of the primary end point

were nearly identical if enrollment occurred more than 4 hours after presentation (primary end point: 9.5% vs 9.8%; key secondary end point: 11.2% vs 12.1%; P = not significant). Patients who presented at local hospitals fared similarly to those presenting at Tertiary care centers with respect to both end points. Among patients who underwent PCI, an unadjusted post hoc analysis demonstrated fewer deaths or MIs at 30 days (8.0%) with early routine eptifibatide compared with a delayed provisional approach (10.5%). Routine early eptifibatide increased rates of bleeding (TIMI major or minor, 4.3% vs 1.9%; GUSTO moderate or severe, 5.1% vs 2.7%; P b .001 for both) and transfusion (8.6% vs 6.7%, P = .001).

Thus, the EARLY ACS trial provided a clear answer for emergency physicians to the main question: In general, a strategy of delayed, provisional use of eptifibatide after angiography was similar in efficacy and safer than routine, early use upstream. For practicing clinicians, it is important to emphasize that patients should be treated aggressively with the other guideline-recommended therapies and under- go angiography by 96 hours, with judicious use of a GP IIb/ IIIa inhibitor before PCI to ensure similar results to those observed in the trial.

A number of factors likely contributed to the lack of superiority of the early, routine strategy, including a convergence of GP IIb/IIIa inhibitor therapy due to delayed provisional use of eptifibatide after angiography but before PCI, high use of optimal medical co-therapies, and patient factors that did not favor early administration of a GP IIb/IIIa inhibitor (eg, 41% did not undergo PCI). On the other hand, the trial also raised questions regarding whether some subgroups of patients (eg, those who could be treated very early after symptom onset, with elevated troponin levels and diabetes, and with known anatomy who were very likely to undergo PCI) might still benefit from early upstream use. Further analyses are ongoing to explore these important issues.

Discussion

Dr Gerard X. Brogan, Jr (Medical Director, Forest Hills Hospital; Associate Professor of clinical emergency Med- icine NYU School of Medicine, New York, NY): At the end of the day, the major benefit, after 15 years of working with

Table 3 End points at 96 hours and 30 days in EARLY ACS [17]

Through 96 h

Early Ept (n = 4722)

Delayed Ept (n = 4684)

P

Through 30 d

Early Ept

Delayed Ept

P

Death, MI, RIUR, TBO a

439 (9.3)

469 (10.0)

0.23

Death, MI, RIUR

398 (8.4)

438 (9.4)

0.11

592 (12.5)

647 (13.8)

0.065

Death or MI b

354 (7.5)

390 (8.3)

0.13

528 (11.2)

578 (12.3)

0.079

Ept indicates eptifibatide; RIUR, recurrent ischemia requiring urgent revascularization; TBO, thrombotic bailout. Data from N Engl J Med. 2009;360:2176-90.

a Primary end point at 96 hours.

b Key secondary efficacy end point at 30 days.

these agents [GP IIb/IIIa inhibitors], has to do with minimizing troponin leaks in PCI.

Dr Cindy L. Grines (Vice-Chief, Cardiology, Academic Affairs, William Beaumont Hospital, Royal Oak, MI): I agree.

Dr Gerard X. Brogan, Jr: When a patient arrives in the ED with a positive troponin level, it is going to be tough to identify a second infarction if an early PCI is performed.

Dr Robert P. Giugliano: Yes, and that is critical in understanding the unusual shape of the Kaplan-Meier event curves in the first 96 hours (Fig. 2). There were few events in the first 16 hours because angiography occurred on average at 21 hours, and since 84% had a positive troponin assay at baseline, it took some time for the troponin level to decline before we could detect a re- elevation (most commonly post-PCI). The secondary end point (death or MI through 30 days) is more straightfor- ward to interpret….I’d like to get your opinions on the results in the key subgroups (Fig. 3).

Dr Marc Cohen (Director, Division of Cardiology, Newark Beth Israel Medical Center, Newark, NJ; Professor of Medicine, Mount Sinai School of Medicine, New York, NY): Along those lines, I would like to see the results among troponin-positive patients diagnosed within 3 hours of presentation.

Dr Robert P. Giugliano: I don’t have the data for that sub- subgroup (which is small and underpowered), but I can say that certain subgroups (those with diabetes, elevated troponin levels at baseline, younger patients, treated earlier) did tend to show results similar to those we have seen in prior GP IIb/ IIIa inhibitor trials. Since this is not the first study in this population with a GP IIb/IIIa inhibitor, I think it makes the

Fig. 2 Kaplan-Meier curves for the primary efficacy end point (all-cause mortality, myocardial [re]infarction, recurrent ischemia requiring urgent revascularization, or thrombotic bailout through 96 hours). The odds ratio for early eptifibatide vs delayed provisional eptifibatide was 0.92 (95% CI, 0.80-1.06; P = .23). P values were calculated using log rank tests that adjusted for intended early clopidogrel use [17]. Data from N Engl J Med. 2009;360:2176-90. Supplementary Appendix 3, accessed at http://content.nejm.org/ cgi/content/full/NEJMoa0901316/DC1, updated April 14, 2009.

most sense for us to take a Bayesian approach, that is, to consider these results in the context of earlier studies.

Recent advances: implications for ED care of the ACS patient

Presenter: Gerard X. Brogan, Jr, MD

An assessment of the value of upstream antiplatelet therapy can be separated into 2 broad issues: First, what therapeutic options are suggested by the results of clinical trials before EARLY ACS? Second, how do the results of EARLY ACS change these recommendations?

The benefits of early administration of GP IIb/IIIa inhibitors were demonstrated in an early meta-analysis of 3 pivotal trials: PURSUIT, CAPTURE, and PRISM-PLUS [27]. Each trial individually demonstrated a significant reduction in death or nonfatal MI in patients randomly assigned to a GP IIb/IIIa inhibitor compared with placebo. The meta-analysis of all 3 trials showed a 1.4% absolute risk reduction for the composite of death or nonfatal MI during the 72 hours before PCI and a 3.1% absolute risk reduction during the 48 hours after PCI (Fig. 4), suggesting that while early treatment with GP IIb/IIIa inhibitors provided consid- erable clinical benefit, the benefit is even larger after PCI. In the PURSUIT trial, considerable benefit was associated with undergoing PCI within 2 to 6 hours of randomization, again suggesting that early treatment provides considerable value in patients with ACS [19]. Similarly, Bhatt and Topol [28] showed a benefit gradient associated with time to PCI among patients enrolled in the PURSUIT trial, in that eptifibatide administration was associated with a 2.8% benefit vs placebo among patients who underwent PCI within 6 hours of admission, and a 2.3%, 1.7%, and 0% benefit among those undergoing PCI from 6 to 12, 12 to 24, and more than 24 hours after admission. The results of PRISM-PLUS and PARAGON-B also support early intervention [29,30]. Meanwhile, the GUSTO-IV ACS trial of 7800 patients with ACS receiving aspirin or heparin (low-molecular- weight heparin [LMWH] or unfractionated) who were not scheduled for early revascularization found no benefit for abciximab [31]. Although this trial targeted a high-risk population, the event rate was lower than expected, and enrollment criteria may have allowed the entry of patients without active coronary artery disease.

The benefits of clopidogrel in patients with NSTE ACS have been demonstrated in multiple clinical trials, including CURE (class I, LOE A). This trial showed that 300 mg clopidogrel plus aspirin compared with placebo plus aspirin, administered to 12 562 patients within 24 hours after the onset of symptoms, was associated with a significant 20% risk reduction for the composite of death from cardiovascular causes, nonfatal MI, or stroke at 1 year [12]. Notably, ischemic end points were already reduced within 24 hours of randomization, again supporting the concept that early antiplatelet treatment provides considerable benefit. The use of clopidogrel is complicated by the fact that it must be started

Fig. 3 Results for the secondary end point of death or MI at 30 days in the EARLY ACS trial [17]. Reprinted with permission from N Engl J Med. 2009;360:2176-90. Copyright (C) 2010 Massachusetts Medical Society. All rights reserved.

early to achieve post-PCI benefit–in many cases, before the decision is made whether the patient will undergo PCI or CABG [7]. Overall, it can be expected that at 1-month follow- up, early treatment prevents approximately 10 major cardiac events (death, MI, or urgent target vessel revascularization) per 1000 patients treated while causing an increase in the rate of minor TIMI bleeds after CABG of 1.5 per 1000 patients treated [12,32,33].

Although clopidogrel is effective in broad populations, concerns exist regarding variability of response. The value of aggressive antiplatelet intervention was demonstrated in the CLEAR PLATELETS study (LOE B) [34], in which, among 120 patients undergoing elective coronary stenting, 600 mg clopidogrel produced superior inhibition compared with 300 mg at all time points [33]. Addition of the GP IIb/IIIa

inhibitor eptifibatide was associated with a 2-fold or higher increase in platelet inhibition compared with clopidogrel alone at either dosage up to 24 hours after stenting and with significant reductions in release of CK-MB. Thus, even in this patient population at low risk for periprocedural events, aggressive antiplatelet intervention was clearly associated with a reduction in release of markers of Myocardial necrosis. Numbers were too small to draw any conclusions about effects on bleeding.

Together, these data suggest that the choice of antiplatelet therapy (eg, dual therapy with aspirin plus clopidogrel, dual therapy with aspirin plus a GP IIb/IIIa inhibitor, or triple therapy with all 3 agents) should be driven by underlying patient risk–both of ischemic and hemorrhagic complica- tions (class I, LOE A). Triple therapy should be preferred in

Fig. 4 Kaplan-Meier curves showing the cumulative incidence of death or nonfatal MI in patients randomly receiving glycoprotein IIb/IIIa inhibition or placebo in 3 pivotal trials (PURSUIT, CAPTURE, and PRISM-PLUS). Data are shown for the 72 hours before and the 48 hours after PCI [26]. Reproduced with permission from Circulation. 1999;100:2045-8.

patients who are troponin-positive, unless there is an elevated bleeding risk (such as in the very elderly, those with end- stage renal disease, or with Severe anemia) or a high likelihood of near-term CABG.

Discussion

Dr Charles V. Pollack, Jr (Professor of Emergency Medicine, University of Pennsylvania School of Medicine; Chairman of Emergency Medicine, Pennsylvania Hospital, Philadelphia): Let me just ask the cardiologists around the table: What is your relationship with your emergency physicians? In your ED, do you have a unified, standard pathway for the troponin-positive patient?

Dr Timothy D. Henry (Director of Research, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, Minneapolis, MN): We have developed standardized ED protocols for most situations. For STEMI patients, the pathway is very standardized, and we rarely get calls from the ED. The non-STEMI standardized protocol took years to develop and is far more difficult to implement. The protocol, which was put in place 6 months ago, consists of aspirin 325 mg, clopidogrel 600 mg, and an IV bolus of unfractionated heparin (UFH).

Dr Charles V. Pollack, Jr: Outside academic centers, emergency physicians often are not empowered to make these decisions without discussion with a cardiologist. Such a protocol takes a lot of decision-making pressure off the emergency physician but of course may also delay Optimal care.

Dr Timothy D. Henry: We tried to make it simple, recognizing the work load of emergency physicians and the broad range of different cases they see every day.

Dr Gerard X. Brogan, Jr: We try to take the world of possibilities and narrow them down to a few, on the premise that there are a number of options. We have a pathway that

took 2 years to develop and is predicated on guideline recommendations. Where the guidelines suggest that 2 or more agents have the same class I recommendation, we allow the alternative option within the framework of the pathway.

Dr Charles V. Pollack, Jr: Is the pathway followed consistently?

Dr Gerard X. Brogan, Jr: You would be amazed at the number of issues that mitigate our ability to properly implement the pathway. In general, however, the ED staff know that a prespecified pathway exists for their use.

Dr Cindy L. Grines: Do they call the cardiologist to ask specific questions about when and how to start clopidogrel or GP IIb/IIIa inhibitors, or do they make that decision on their own?

Dr Gerard X. Brogan, Jr: In patients with STEMI, the ED physician makes the decision, to minimize delay. In patients with UA, the risk stratification process is a little more complex, and it is key to have this process take place at the time of initial ED evaluation.

Dr Charles V. Pollack, Jr: Dr Brogan, is there an option to start a GP IIb/IIIa inhibitor in the ED?

Dr Gerard X. Brogan, Jr: Our protocol ensures rapid intervention when necessary, and this allows for rapid risk stratification and identification of UA NSTEMI patients, whom current guidelines have identified as benefiting from early antiplatelet therapy (class I, LOE A) [5].

Dr Charles V. Pollack, Jr: Of course, the precise definition of “early” is something the guidelines don’t provide, which is why we are still performing trials like EARLY ACS. Will the results of EARLY ACS affect your practice?

Dr Gerard X. Brogan, Jr: Our practice has been to rapidly identify high-risk patients who, according to a number of previous trials and clinical guidelines, are likely to benefit from GP IIb/IIIa inhibitor therapy and to initiate therapy at

that time, with a concurrent assumption that the patient will be transitioned to the cath lab within 24 hours. While EARLY ACS might indicate that our timing (vs cath-lab initiated) does not provide added benefit, there may be subsets of patients that would see benefit. As this is not a discussion regarding treat or not treat but, rather, timing, we remain comfortable achieving effective antiplatelet therapy as early as possible. Patients with creatinine clearance (CrCl) N50 mL/kg may receive full-dose eptifibatide, and patients on dialysis should be excluded from consideration for receiving eptifibatide. For nondialysis patients with CrCl b50 mL/kg, the infusion should be reduced by 50% (with no change in the bolus dose). We would not exclude a troponin- positive patient from receiving glycoprotein IIb/IIIa therapy solely on the basis of a CrCl of 40 mL/kg, for example. However, it is important to keep in mind that patients with impaired renal function are at increased risk of and should be monitored for bleeding.

Defining the significance of bleeding in ACS clinical trials

Presenter: Marc Cohen, MD

Director, Division of Cardiology, Newark Beth Israel Medical Center, Newark, NJ; Professor of Medicine, Mount Sinai School of Medicine, New York, NY (a comprehensive summary of Dr Cohen’s presentation and discussion has been published elsewhere [9]).

Data suggest that patient factors of increased age, female sex, preexisting anemia, renal insufficiency, and aggressive antiplatelet therapy (eg, heparin plus GP IIb/IIIa inhibitors vs bivalirudin) are independent risk factors for major bleeding and have implications for emergency practice [7,35] (eg, use of fondaparinux in patients at increased risk for bleeding carries a class I, LOE B recommendation). These data have led some to suggest that agents with less antiplatelet efficacy in ischemia may improve outcomes overall through reducing major bleeding risk.

Questions regarding the relative impact of ischemic efficacy vs reduced bleeding can be answered in part by the results of the OASIS-5 trial, which randomly assigned 20 078 patients with ACS to receive fondaparinux (2.5 mg/d) or enoxaparin (1 mg/kg twice daily) for a mean of 6 days and evaluated the composite of death, MI, or refractory ischemia at 9 days [36]. Mortality results at 9 days (1.9% vs 1.8%; hazard ratio [HR], 0.95; 95%

confidence interval [CI], 0.77-1.17) and 30 days (2.9%

vs 3.5%; HR, 0.83; 95% CI, 0.71-0.97; P = .02)

contributed to class IA (European Society of Cardiology) and IB (ACC/AHA) recommendations for fondaparinux in patients undergoing an early invasive strategy [5,6]. Overall, there was no difference in Ischemic events through 9 days between the fondaparinux and enoxaparin groups; however, major bleeding through 9 days occurred in only 2.2% of fondaparinux patients compared with 4.1% of enoxaparin patients (P = .001), with more

catheter-related thrombi in the fondaparinux group, suggesting that fondaparinux patients who are catheterized will require more heparin [7,36]. Similarly, results in patients with STEMI from the HORIZONS-AMI trial (n = 3602) indicated that bivalirudin was associated with less bleeding but also with significantly more stent thrombosis at 24 hours (although this difference was not significant at 30 days) [37]. These data highlight the importance of looking beyond the primary efficacy and safety end points and illustrate that reduced bleeding should be one of many factors involved in making therapeutic decisions.

Reduced bleeding does not necessarily equate to Mortality benefit. For example, the ACUITY trial in 13 819 patients with ACS demonstrated a significant reduction in the rate of major bleeding: from 5.7% with UFH, enoxaparin, and GP IIb/IIIa inhibition to 3.0% with bivalirudin alone (Fig. 5) [38]. However, this reduction did not translate into a mortality benefit; in fact, the risk for death was slightly lower (1.3% vs 1.6%) in the group receiving UFH/ enoxaparin/GP IIb/IIIa inhibitor.

Although the relationship between bleeding and mortality is complex, it is clear that strategies are available to minimize risk for bleeding while maximizing anti-ischemic benefit. Data from the ESPRIT trial show that in 2064 patients undergoing stenting, higher activated clotting times did not improve efficacy and were associated with increased bleeding [39]. Optimizing the dosage of heparin, aided by close collaboration among the ED, the treating cardiologist, and the catheterization laboratory, can minimize bleeding risk without increasing ischemic events [7]. A second strategy for minimizing bleeding risk while maximizing anti-ischemic benefit is to ensure that GP IIb/IIIa inhibitors are dose-adjusted according to renal function (LOE B). Bleeding complications may also be reduced with radial access, smaller sheath size, and timely sheath removal [40].

Fig. 5 Reductions in major bleeding and mortality in the ACUITY trial [37]. ACUITY indicates Acute Catheterization and Urgent Intervention Triage strategY. Data from N Engl J Med. 2006;355:2203-16.

Discussion

Dr Marc Cohen: All of us would really appreciate tricks and tools to minimize bleeding, but to adopt as a matter of religion the concept that all bleeding is bad and the line is clear is a little too simplified.

Dr Neal S. Kleiman: There may be an underlying pathophysiology in patients with renal disease that predis- poses them to bleeding. We know that patients with renal disease often have calcified arteries. The rigidity of the femoral artery could be enough to predispose to groin bleeding. Bleeding risk in these patients is certainly multifactorial, but I think inappropriate dosing contributes to the problem.

Dr Marc Cohen: In the STEEPLE trial, the bleeding rate literally doubled if we didn’t modify the dosing for creatinine clearance [41]. Any agent, including bivalirudin, that has some component of renal clearance can have an adverse impact in patients with renal insufficiency.

Dr Robert P. Giugliano: When you ask whether major bleeding is associated with death, I think Intracranial Hemorrhage is. But with non-ICH major bleeding, the relationship and causal path are complicated, and there is a lot of confounding.

Dr Marc Cohen: In data from the CRUSADE registry, we see almost a linear relationship between bolus dosing of heparin and major bleeding [42]. I would think it is almost unethical nowadays not to adjust the heparin dose based on weight, and in fact, the current ACC/AHA guidelines recommend this [5].

Dr Cindy L. Grines: If you don’t give a drug, of course the patient is not going to bleed, but is that necessarily the right thing for the patient?

Dr Timothy D. Henry: We always consider the benefit of upfront clopidogrel in terms of its effect on decreasing ischemia, thinking you may obviate the need for a GP IIb/IIIa inhibitor. We do not always consider the additional risk of bleeding with clopidogrel in addition to aspirin and a GP IIb/ IIIa inhibitor.

Dr Marc Cohen: In EARLY ACS, we clearly saw an increase in major bleeding as defined by TIMI criteria. Ironically, though, with regard to life-threatening GUSTO severe bleeding, we saw a relatively low level that was pretty equivalent between the two.

Patient profile most likely to benefit from Upstream administration of GP IIb/IIIa inhibitors: a panel discussion

Dr Charles V. Pollack, Jr: In light of the results of the EARLY ACS trial, do we still believe that some patients are appropriate candidates for upstream GP IIb/IIIa therapy? This is a particularly salient question for me, given that I have been using upstream IIb/IIIa therapy in NSTEMI patients for years now and have felt very comfortable with it, based on the outcomes of multiple earlier clinical trials. Did the earlier

studies show an indication–if not clear-cut evidence–of upstream benefits, or were they just wrong? Or are they outdated in the context of contemporary therapy? Likewise, the data we saw in the CRUSADE registry indicated that at least in troponin-positive patients, there is benefit with GP IIb/ IIIa therapy upstream; was that wrong [43]? What is the thinking around the table before we go further?

Dr Timothy D. Henry: EARLY ACS does not answer the question I still have in my mind regarding troponin-positive patients who are treated within 3 hours of presentation. Is there or is there not benefit associated with upstream vs delayed treatment in this scenario? I would like to see these patients stratified into 2 subsets: those who were given clopidogrel on entry to the ED and those who were not.

Dr Robert P. Giugliano: I have some partial answers, based on subgroup data from the EARLY ACS trial. When we analyzed patients who were randomized within 4 hours of presentation (compared with those randomized N4 hours after presentation), there was a tendency toward more benefit. However, the formal statistical test for interaction showed no significant difference. There appeared to be no signal of benefit among the 14% of patients who were troponin-negative, so you are right to focus on those who are troponin-positive at baseline. Lastly, the use of (or, as we analyzed it, the intention to administer) clopidogrel early did not have a strong influence on the efficacy of early, routine eptifibatide. What you are asking about is a triple subgroup (early presenter, elevated baseline troponin, stratified by clopi- dogrel use), which becomes a much smaller subgroup than the trial is powered to analyze. That’s why I said I have some partial answers. (See Table 4.)

Dr Timothy D. Henry: I think we need to look at only troponin-positive patients and compare those treated within 4 hours of presentation vs those treated more than 24 hours after presentation.

Dr Charles V. Pollack, Jr: Then you are really narrowing down the patient population. You are talking about a subset of a subset of a subset of a subset.

Table 4 Key questions for future research

Which (if any) higher-risk patients are likely to benefit most from upstream use of GP IIb/IIIa inhibitors? Might this be indicated by a particular level of Troponin elevation?

Were potential benefits of early GP IIb/IIIa administration in EARLY ACS obscured by administration of potent background antiplatelet therapy? How did clopidogrel dosing patterns affect outcomes?

Can an optimal amount and time of clopidogrel dosing be determined for patients with UA/NSTEMI?

Will prasugrel be beneficial in high-risk patients with non-ACS reasons for undergoing PCI (eg, multiple stents, small vessels, poor ventricles)? Will it be appropriate for short-duration use in patients at high risk?

Dr Timothy D. Henry: Based on all the EARLY ACS data, I would suggest that this population may be the one most likely to benefit from upstream therapy.

Dr Charles V. Pollack, Jr: So, cardiologists around the table–do you think the earlier data were wrong, or do you think that so much has changed regarding how we manage patients today that the benefit has been diluted by other things we do?

Dr Marc Cohen: For me, the major portion of the answer is just change–and clopidogrel has been responsible for most of that change. Many patients are getting clopidogrel 600 mg upfront, so they already have antiplatelet benefit “on board.” Dr Timothy D. Henry: That is the key point. Most physicians are not loading with 600 mg clopidogrel. Is the message that you need Dual antiplatelet therapy upstream, either aspirin and clopidogrel or aspirin and GP IIb/IIIa

inhibitor, vs aspirin alone?

Dr Marc Cohen: I would suggest that the data argue exactly the opposite: early clopidogrel has a greater effect with early GP IIb/IIIa inhibitors.

Dr Gerard X. Brogan, Jr: It would be a mistake to assume that there is bioequivalence between aspirin/clopidogrel and aspirin/eptifibatide. Historically, we have seen benefit associated with synergies among agents, such as GP IIb/ IIIa inhibitors with clopidogrel, which is far from potent in terms of absolute platelet inhibition.

Dr Deborah B. Diercks: From the ED perspective, “early” clopidogrel means a lot of different things. “Early,” to me, means “as soon as I see the patient.” To somebody else, early means prior to catheterization, and I do not think we have a good understanding of when that is.

Dr Neal S. Kleiman: I would not put very much money on the clopidogrel issue. One can construct a very plausible argument that biologically, GP IIb/IIIa inhibitors and thienopyridines do entirely different things to the platelet. There are striking differences in the amount of aggregation inhibition you get with clopidogrel (no matter how much you give) and with a GP IIb/IIIa antagonist when you use the doses that were used in this study.

Dr Charles V. Pollack, Jr: To many emergency physicians, the idea is that you need to give something that provides more antiplatelet activity than aspirin.

Dr Gerard X. Brogan, Jr: My question is whether dual antiplatelet therapy upstream is better than single-agent treatment. And if you were going to choose dual antiplatelet therapy, are aspirin and clopidogrel or aspirin and a GP IIb/ IIIa inhibitor more effective?

Marc Cohen: Let’s start at the beginning. The point of the EARLY ACS trial was to ask whether adding a GP IIb/IIIa receptor blocker on top of current therapy makes a difference. The implicit understanding is that current therapy is a full dose of clopidogrel given early. I do not know how we can get around the fact that the design of this trial prevents us from making a statement about the value of a GP IIb/IIIa inhibitor on top of full doses of other drugs when the population is being treated, in essence, in 2 different ways.

Dr Charles V. Pollack, Jr: It is tricky, because if you mandate clopidogrel loading, then you have to mandate a dose. Dr Marc Cohen: I do not have a good solution to this issue. You choose your battles when you design trials. We have to be really careful making general remarks about this trial, for example, “adding a GP IIb/IIIa inhibitor does not matter when you use clopidogrel.” The fact is only half the patients in the United States get clopidogrel. As a result, we as physicians must be careful about interpretive conclu- sions. The second matter that is interesting to me is the shape of the curve in the EARLY ACS trial. At least among patients who were troponin-positive, if there was a difference in the first 24 hours, you should have been able

to see it early.

Dr Neal S. Kleiman: Marc, you have noted that adjudication of early events is challenging. Even in the past, when the delay was longer, there was difficulty with this. Today people are getting to the lab even earlier. If you use creatine kinase as your measure of infarction, patients will not be anywhere near baseline when you look for reinfarction.

Dr Deborah B. Diercks: Maybe it would be interesting to look at the evolving MI patient. What happens to those who are not troponin-positive when they present but are actually having ongoing infarction and their troponin level is elevating throughout their course? That is a different clinical picture from somebody who comes in with elevated troponins.

Dr Robert P. Giugliano: Patients with evolving MIs (initially troponin negative) were a small group in the EARLY ACS trial. While this is a very important question, the small numbers in this trial really limit us.

Dr Deborah B. Diercks: I think the problem, from the perspective of the ED setting, is that for patients with stroke, we are taught that time is brain; with STEMI, time is muscle, but we can’t seem to translate that urgency to non-STEMI. Nobody has ever said that time, from the minute the patient is admitted to the minute we initiate therapy, actually matters for NSTEMI outcomes. I think it is clear that initiating therapy prior to PCI impacts outcome, but not from the minute the patient is admitted to the ED.

Dr Gerard X. Brogan, Jr: It is interesting to go back to the INTERACT trial, which used the surrogate marker of Holter monitoring and ST-segment deviation in 746 patients with high-risk NSTE ACS in the first 48 hours. The effect of a combination of LMWH and eptifibatide was effective [44]. Dr Charles V. Pollack, Jr: Dr Giugliano, is there any evidence that the 70% enrollment outside the United States

in EARLY ACS had an impact on the results?

Dr Robert P. Giugliano: Those analyses are ongoing. The treatment effect was somewhat larger (but not statistically significantly different) in Western Europe than in the United States.

Dr Charles V. Pollack, Jr: I would like to wrap up this discussion by considering an answer to the question I posed earlier: Which patients should receive upstream therapy in the emergency department? EARLY ACS has shown us that routine early use is not indicated, and we await the answer to

Table 5 Key observations

Practice guidelines are important and should be followed whenever possible and appropriate. However, in circumstances in which the guidelines are vague, lacking, or do not incorporate the newest clinical trial data, there will still be controversy.

The results of EARLY ACS suggest that in general, a strategy of delayed, provisional use of eptifibatide after angiography was similar in efficacy and safer than routine early (upstream) use among high-risk patients with UA/NSTEMI.

A small subgroup of patients (early presenters, with elevated baseline troponin levels, and/or stratified by clopidogrel use) may have better outcomes with early vs delayed provisional administration of eptifibatide, but the EARLY ACS trial was not powered to detect a treatment difference in this subgroup.

Based on analysis of multiple trials, triple therapy (clopidogrel, aspirin, and a GP IIb/IIIa inhibitor) should be preferred in patients with UA/NSTEMI who are troponin-positive, unless there is an elevated bleeding risk (as is seen in the very elderly, those with end-stage renal disease, or with severe anemia) or a high likelihood of near-term CABG surgery.

the question of which (if any) higher-risk patients might benefit from upstream use (see Table 5).

Dr Cindy L. Grines: I wonder if there is a level of troponin above which patients would derive more benefit. I am struck by the fact that the bar has been lowered significantly in terms of what we are calling abnormal troponin levels. We are getting a lot of patients who have positive troponins and negative CK-MBs–what do you do with these patients?

Dr Robert P. Giugliano: There are some data on that. The positive troponin/negative CK-MB patients behave more like patients with true MIs, that is, those with positive troponins and positive CK-MBs, whereas the reverse group (positive CK-MB/negative troponins) is more similar to the negative/ negative group.

Post-meeting observations

[These comments are included here because of their relevance to roundtable topics. They were not part of the main discussions because the data from the PLATO and OASIS 7 trials were presented after the June 2009 roundtable meeting.] Dr Neal S. Kleiman: The PLATO trial in 18 624 patients with ACS compared clopidogrel (300-600 mg loading dose, 75 mg/day thereafter) with ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) [45]. At 12 months, the primary end point (cardiovascular events and death) was reduced from 11.7% with clopidogrel to 9.8% with ticagrelor (HR, 0.84; P b .001). Use of ticagrelor was also associated with a reduction of the predefined secondary end points of MI (5.8% vs 6.9%; HR, 0.84; P = .005) and death from vascular causes (4.0% vs 5.1%; HR, 0.79; P = .001). However, ticagrelor did not prevent stroke (1.5% vs 1.3%; P = .22), a predefined secondary end point, and was associated with more discontinuations for adverse events (7.4% vs 6.0%; P = .001). Rates of CABG-related and trial-defined and

TIMI major bleeding were similar, although ticagrelor was associated with increased rates of non-procedure-related major bleeding (4.5% vs 3.8%; P = .03), the secondary safety end point. Ventricular pauses >=3 seconds were seen more frequently in patients randomly assigned to ticagrelor (5.8% vs 3.6%; P = .01). Slightly more than a quarter of patients received a GP IIb/IIIa inhibitor; the relevance of ticagrelor to other current treatments such as GP IIb/IIIa inhibitors remains to be seen.

CURRENT-OASIS 7 recently reported preliminary results in 25 087 patients with ACS managed with an early invasive strategy [46]. This 2 x 2 factorial study was designed to evaluate both the efficacy and safety of a high- vs low-dose aspirin regimen as well as to compare double- with standard-dose clopidogrel, among patients with ST- or NSTE ACS, with all patients randomized within 24 hours of symptom onset. In its primary analysis, CURRENT-OASIS 7 showed a significant interaction for the primary end point (a composite of Cardiovascular death, MI, and stroke) between high- and low-dose aspirin and double- and standard-dose clopidogrel groups (P = .043), with patients randomly assigned to high-dose aspirin having lower rates of the primary end point on double-dose clopidogrel compared with standard-dose clopidogrel; this difference was not seen in patients randomly assigned to low-dose aspirin. While analyses of the pooled strata (high- vs low-dose aspirin and double- vs standard-dose clopidogrel) showed no differences in the primary efficacy end point, a postrandomization subgroup analysis of patients who underwent PCI showed a potential benefit for double- vs standard-dose clopidogrel. This suggests a potential effect of varying clopidogrel dosing patterns on the results seen in EARLY ACS.

Conclusions

Management of ACS in the upstream setting is driven by ongoing risk stratification for both ischemic events and adverse responses (primarily bleeding complications) to the therapy that is given. While guidelines and clinical registries can paint broad outlines within which we should practice, there is no substitute for a prospective, multidisciplinary, institution-specific, consistent, evidence-based approach to patient management. Emergency physicians should stay current with new clinical data in ACS, with guidelines documents as they are published, and–just as importantly– with data from their own institutions. Just as practitioners of both cardiology and emergency medicine exchanged ideas on this panel, optimal patient management occurs when a smooth, consistent, evidence-based continuum of care is created by upstream and downstream providers collaborating in the management of ACS.

Acknowledgment

Editorial assistance was provided by Rina Kleege, MS, and Rob Coover, MPH, of AdelphiEden Health

Communications. This assistance and the roundtable on which the manuscript is based were funded by Schering Corp, now Merck & Co.

References

  1. Tapson VF, Hyers TM, Waldo AL, et al. NABOR (National Anticoagulation Benchmark and Outcomes Report) Steering Commit- tee. antithrombotic therapy practices in US hospitals in an era of practice guidelines. Arch Intern Med 2005;165:1458-64.
  2. Aithal GP, Day CP, Kesteven PJL, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999;353: 717-9.
  3. Higashi MK, Veenstra DL, Kondo LM, et al. Association between CYP2C9 Genetic variants and anticoagulation-related outcomes during Warfarin therapy. JAMA 2002;287:1690-8.
  4. Geisler T, Schaeffeler E, Dippon J, et al. CYP2C19 and nongenetic factors predict poor responsiveness to clopidogrel loading dose after coronary stent implantation. Pharmacogenomics 2008;9:1251-9.
  5. Anderson JF, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non- ST-elevation myocardial infarction–executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/non-ST-elevation myocardial infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interven- tions, and Society of thoracic surgeons. J Am Coll Cardiol 2007;50: e1-e157.
  6. Bassand JP, Hamm CW, Ardissino D, et al. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The Task Force for the Diagnosis and Treatment of Non- ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J 2007;28:1598-660.
  7. Pollack Jr CV, 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;51:591-606.
  8. ACC/AHA Task Force on Practice Guidelines. Manual for ACC/AHA Guideline Writing Committees. Methodologies and policies from the ACC/AHA Task Force on Practice Guidelines. Available at: http:// circ.ahajournals.org/manual/manual_introltr.shtml [Accessed April 15, 2010].
  9. Giugliano R, Pollack C, Brogan G, et al. Acute coronary syndromes: from the emergency department to the catheterization laboratory– integrating evidence from recent ACS/NSTEMI trials into clinical practice. An evidence-based review of recent clinical trial results and report on a roundtable discussion. J Interven Cardiol 2010 [in press].
  10. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15.
  11. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and Medical patients. BMJ 1994;308:235-46.
  12. Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502.
  13. Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 2006;27:519-26.
  14. Giugliano RP, Girarldez RR, Morrow DA, et al. Relations between bleeding and outcomes in patients with ST-elevation myocardial infarction in the ExTRACT-TIMI 25 Trial. Eur Heart J 2010;31: 2103-10.
  15. Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723-31.
  16. Bonello L, Camoin-Jau L, Armero S, et al. Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent stent thrombosis. Am J Cardiol 2009;103:5-10.
  17. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354-62.
  18. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176-90.
  19. PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998;339:436-43.
  20. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and Non-ST-segment elevation myocardial infarction–summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol 2002;40:1366-74.
  21. Hoekstra JW, Roe MT, Peterson ED, et al. Early glycoprotein IIb/IIIa inhibitor use for non-ST-segment elevation acute coronary syndrome: patient selection and associated treatment patterns. Acad Emerg Med 2005;12:431-8.
  22. Mehta RH, Roe MT, Chen AY, et al. Recent trends in the care of patients with non-ST-segment elevation acute coronary syndromes: insights from the CRUSADE initiative. Arch Intern Med 2006;166:2027-34.
  23. Stone GW, Bertrand ME, Moses JW, et al. ACUITY Investigators. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: The ACUITY Timing Trial. JAMA 2007;297:591-602.
  24. Pollack Jr CV, Hollander JE, Chen AY, et al. Non-ST-elevation myocardial infarction patients who present during Off hours have higher risk profiles and are treated less aggressively, but their outcomes are not worse: a report from Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines CRUSADE initiative. Crit Pathw Cardiol 2009;8:29-33.
  25. Smith Jr SC, Feldman TE, Hirshfeld Jr JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006;47:216-35.
  26. Silber S, Albertsson P, Aviles FF, et al. Guidelines for Percutaneous coronary interventions: the Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005;26:804-47.
  27. Boersma E, Akkerhuis KM, Theroux P, Califf RM, Topol EJ, Simoons ML. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST- elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation 1999;100:2045-8.
  28. Bhatt DL, Topol EJ. Current role of platelet glycoprotein IIb/ IIIa inhibitors in acute coronary syndromes. JAMA 2000;284: 1549-58.
  29. PRISM-PLUS Investigators. Inhibition of the platelet glycoprotein IIb/ IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators. N Engl J Med 1998;338:1488-97.
  30. McKay RG, Boden WE. Small peptide GP IIb/IIIa receptor inhibitors as upstream therapy in non-ST-segment elevation acute coronary syndromes: results of the PURSUIT, PRISM, PRISM-PLUS, TACTICS, and PARAGON trials. Curr Opin Cardiol 2001;16:364-9.
  31. GUSTO IV-ACS Investigators. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV- ACS randomised trial. Lancet 2001;357:1915-24.
  32. Steinhubl SR, Berger PB, Mann 3rd JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411-20.
  33. Mehta SR, Yusuf S, Peters RJG, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-33.
  34. Gurbel PA, Bliden KP, Zaman KA, Yoho JA, Hayes KM, Tantry US. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005;111:1153-9.
  35. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. J Am Coll Cardiol 2007;49:1362-8.
  36. Yusuf S, Mehta SR, Chrolavicius S, et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464-76.
  37. Stone GW, Witzenbichler B, Guagliumi G, et al. HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocar- dial infarction. N Engl J Med 2008;358:2218-30.
  38. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16.
  39. ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo- controlled trial. Lancet 2000;356:2037-44.
  40. Cantor WJ, Mahaffey KW, Huang Z, et al. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007;69:73-83.
  41. White HD, Gallo R, Cohen M, et al. The use of intravenous enoxaparin in elective percutaneous coronary intervention in patients with Renal impairment: results from the SafeTy and Efficacy of Enoxaparin in PCI patients, an internationaL randomized Evaluation (STEEPLE) trial. Am Heart J 2009;157:125-31.
  42. Melloni C, Alexander KP, Chen AY, et al. CRUSADE Investigators. Unfractionated heparin dosing and risk of major bleeding in non-ST- segment elevation acute coronary syndromes. Am Heart J 2008;156: 209-15.
  43. Tricoci P, Peterson ED, Chen AY, et al. Timing of glycoprotein IIb/ IIIa inhibitor use and outcomes among patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (results from CRUSADE). Am J Cardiol 2007;99: 1389-93.
  44. Yan AT, Yan RT, Huynh T, et al. Bleeding and outcome in acute coronary syndrome: insights from continuous electrocardiogram monitoring in the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial. Am Heart J 2008;156:769-75.
  45. Wallentin L, Becker RC, Budaj A, et al. PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045-57.
  46. Mehta SR, on behalf of the CURRENT Investigators. CURRENT- OASIS 7: a 2 x 2 factorial randomized trial of optimal clopidogrel and aspirin dosing in patients with ACS undergoing an early invasive strategy with intent for PCI. Presented at 2009 Congress of the European Society of Cardiology; Barcelona, Spain: August 30, 2009.

Leave a Reply

Your email address will not be published. Required fields are marked *