Strategies for Optimizing Outcomes in the NSTE-ACS Patient: The CATH (Cardiac Catheterization and Antithrombotic Therapy
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(PART II) A second group of patients who have received less attention were those who were switched at randomization; approximately three quarters of the patients were on some form of antithrombotic therapy prior to randomization — half of these would have stayed on their initial therapy and half would have switched to the other therapy. In patients who were switched at randomization under controlled, protocol-driven algorithms, there was no significant increase in bleeding complications (or reduction in clinical efficacy) in patients switching from enoxaparin to UFH. Blindly and uncontrollably giving UFH in the catheterization laboratory to LMWH-treated patients (“stacking” therapy) may engender more bleeding events, but appropriately transitioning patients to UFH does not. As shown in SYNERGY, continuing enoxaparin through to the catheterization laboratory appears to be an acceptable alternative (and may be preferred because of its simplicity), but the desire to use UFH in the catheterization laboratory does not preclude using enoxaparin for the initial medical management, as long as such a switch is done in a controlled fashion. Recent attention has also focused more closely on the 2,440 patients in SYNERGY who did not receive any prerandomization therapy, and the 6,138 patients who were not switched at randomization.⁶⁸ The effect of randomized therapy appeared to vary with the type of pretreatment therapy (none, UFH, enoxaparin or both; p = 0.055 for interaction after adjustment for differences in the groups). Patients who received consistent therapy with enoxaparin had a significantly lower likelihood of death or MI at 30 days (p = 0.041) and a trend towards higher bleeding events.⁶⁸ The Fifth Organization to Assess Strategies in Acute Coronary Syndromes (OASIS-5) trial will be subsequently discussed in more detail, but provides important new information on the transition of enoxaparin-treated patients to the catheterization laboratory.⁶⁹ In OASIS-5, 20,078 patients with ACS were randomly assigned to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg/kg bid). Relevant to the transition issue, enoxaparin-treated patients who underwent coronary intervention were supposed to receive no additional therapy if they come to the catheterization laboratory within 6 hours.⁶⁹ However, if they came to catheterization after this time window they received 100 U/kg if no GP IIb/IIIa blocker was given and 70 U/kg if a GP IIb/IIIa antagonist was given. Approximately 53% of patients undergoing PCI in the enoxaparin arm received open-label UFH in this fashion. Importantly, the use of open-label UFH in this way resulted in substantial increases in bleeding complications — an important message perhaps about how not to use UFH in transitioning enoxaparin-treated patients to the catheterization laboratory. The EXTRACT-TIMI 25 study involved 20,506 patients with STEMI treated with fibrinolytic therapy; study subjects were randomized to either weight-based UFH therapy for at least 48 hours or enoxaparin (30 mg IV bolus, 1 mg/kg subcutaneously every 12 hours; dosage adjusted in patients > 75 years by omitting the bolus and reducing the dose to .75 mg/kg) through the index hospitalization.⁴⁷ The primary endpoint was the composite of death or recurrent nonfatal MI through 30 days. While EXTRACT was an MI study rather than a NSTE-ACS study, and not a study of primary PCI, it did include some very important lessons for transitioning patients to the catheterization laboratory. In the overall trial, primary events were significantly reduced in the enoxaparin group (9.9% vs. 12.0% with UFH; p p 47 A recent subset analysis of 4,676 EXTRACT patients coming forward to PCI within 30 days of randomization showed that enoxaparin-treated patients had significantly fewer primary outcome events (10.7% vs. 13.8% with UFH), and no significant increase in TIMI major bleeding, TIMI minor bleeding, total TIMI bleeding and stroke.⁷⁰ A key feature distinguishing these results from those of SYNERGY is that EXTRACT was a blinded trial, and patients coming forward to intervention continued study drug therapy (including a SYNERGY-like transition regimen for enoxaparin patients), and open-label UFH was not used in the catheterization laboratory. Moreover, it also appears that the reduced dosing of enoxaparin used in the elderly was successful in preventing the age-associated increases in bleeding that have been noted in multiple other clinical trials. Covering the “spectrum” of clinical care. A systematic overview of the 6 major trials comparing enoxaparin versus UFH [ESSENCE, TIMI 11B, ACUTE II, Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT), A to Z and SYNERGY] has been reported.⁷¹ This analysis included outcomes for almost 22,000 patients, spanning a variety of different management approaches. Overall, there was no significant mortality difference between enoxaparin and UFH, but there was a significantly lower incidence of the composite of death or MI at 30 days in enoxaparin-treated patients (10.1% vs. 11.0% with UFH; NNT = 107).⁷¹ Given the potential confounding issues of prior antithrombin therapy (highlighted in SYNERGY), a secondary analysis showed similar benefits of enoxaparin in patients not on prior therapy (8.0% vs. 9.4%; NNT 72). There were no differences in the rates of transfusion or major bleeding between enoxaparin and UFH in either the overall population or in patients on no prior antithrombin therapy.⁷¹ Another aspect of the spectrum of care has to do with the management of patients who are transferred from one institution to another, such as from a facility without a catheterization laboratory to a tertiary center with one. There are few studies that have looked at this issue per se⁷² and none that have really focused on the choice of antithrombotic therapy. The INTERACT study, performed in Canada (where such transfers are relatively routine), showed enoxaparin to be clinically superior to UFH for both efficacy and safety.⁷³ As yet, however, specific transfer data from INTERACT have not been reported. There are theoretical advantages to the simpler and potentially-less-prone-to-error use of LMWH instead of UFH in these circumstances, but that remains to be shown prospectively. Hopefully additional data from existing studies that can help clarify this issue will be forthcoming. Panel Recommendations: LMWH (See Figure 6) Primarily medical therapy for UA/NSTEMI • LMWH (enoxaparin) 1 mg/kg subcutaneously every 12 hours preferred • Consider reduced dose in elderly (EXTRACT), impaired renal function • Intravenous bolus not necessary to start Initial medical therapy followed by selective invasive therapy for NSTE-ACS • LMWH (enoxaparin) 1 mg/kg subcutaneously every 12 hours • Consider reduced dose in elderly (EXTRACT), impaired renal function • Intravenous bolus not necessary to start, but can consider adding in catheterization laboratory • SYNERGY transition strategy preferred; No monitoring and no additional UFH if PCI Early-invasive therapy • LMWH (enoxaparin) an option 1 mg/kg SC every 12 hours with a 30 mg IV bolus • Consider reduced dose in elderly (EXTRACT), impaired renal function • SYNERGY transition strategy • Switching to other agents less desirable — no time for proper switch Direct Thrombin Inhibitors Although the combination of anticoagulants (LMWH or UFH) plus a GP IIb/IIIa inhibitor, currently remains an evidence-based standard for managing high-risk patients with NSTE-ACS undergoing PCI, direct thrombin inhibitors have also been evaluated in ACS patients undergoing PCI.^74,75 The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial randomized 6,010 PCI patients (77% in the U.S.) to heparin plus a GP IIb/IIIa blocker (eptifibatide or abciximab) or to bivalirudin alone with the provisional addition of a GP IIb/IIIa blocker if needed in a double-blind, triple-dummy design.⁷⁴ While REPLACE-2 identified a significantly lower rate of “bleeding,” with bivalirudin alone, the results also indicated that patients undergoing low-risk PCI treated with bivalirudin and provisional use of GP IIb/IIIa inhibitors experienced a trend toward higher rates of MI at 30 days versus those treated with UFH heparin and planned GP IIb/IIIa inhibitor therapy (7.0% vs. 6.2%; p = 0.26), including a 41% increase in the occurrence of large MIs (CK-MB > 5x ULN) (2.4% vs. 1.7%; NS).74 More recently, the Acute Catheterisation and Urgent Intervention Triage Strategy (ACUITY) trial was conducted to examine whether or not the use of bivalirudin in place of UFH or LMWH improves outcomes in moderate-to-high risk NSTE-ACS patients heading for early catheterization.⁷⁵ A second question addressed by ACUITY was whether the use of bivalirudin eliminates the need for the routine early (as opposed to deferred) use of a GP IIb/IIIa blocker, or whether the combination of bivalirudin and a GP IIb/IIIa blocker will improve outcomes further. In ACUITY, 13,819 patients were enrolled with moderate- to high-risk NSTE-ACS, all of whom underwent cardiac catheterization within 72 hours; percutaneous or surgical revascularization was performed when appropriate.⁷⁵ Patients were randomized to one of three arms: UFH or enoxaparin plus routine GP IIb/IIIa inhibition; bivalirudin plus routine GP IIb/IIIa inhibition or bivalirudin alone, with GP IIb/IIIa inhibition only given as “bailout”.⁷⁵ In the UFH/enoxaparin plus GP IIb/IIIa inhibition arm, individual investigators chose which agent to use — approximately half used UFH and half enoxaparin. Clopidogrel was recommended, but the dosage and timing were determined by the individual investigators. A total of 60% of patients actually received clopidogrel: 30% were taking it on admission, 20% were given it before randomization and 10% received the drug before going to the catheterization laboratory.⁷⁵ The primary endpoint was a 30-day composite of death, MI or unplanned revascularization for ischemia and major bleeding. Treatment with bivalirudin plus GP IIb/IIIa inhibitors was noninferior to combination therapy with heparin plus GP IIb/IIIa inhibitors using a 25% lower boundary. At 30 days, 11.7% of patients treated with heparin plus GP IIb/IIIa inhibitors and 11.8% of those receiving bivalirudin plus GP IIb/IIIa inhibitors had the composite primary endpoint including death, MI, urgent revascularization or ACUITY major bleeding (p p = 0.93 for superiority).⁷⁵ Both components of the primary endpoint supported the noninferiority of bivalirudin plus GP IIb/IIIa inhibition but not its superiority. Ischemic events occurred in 7.3% of heparin plus GP IIb/IIIa inhibition and 7.7% of patients receiving bivalirudin plus GP IIb/IIIa inhibition (p = 0.007 for noninferiority; p = 0.39 for superiority) and major bleeding occurred in 5.7% and 5.3% of patients, respectively (p = 0.0001 for noninferiority; p = 0.38 for superiority).⁷⁵ Bivalirudin alone was superior to heparin plus GP IIb/IIIa inhibition for the primary combined endpoint, occurring in 10.1% of bivalirudin patients and 11.7% of those treated with the heparin-GP IIb/IIIa inhibitor combination — a 14% relative risk reduction (p = 0.015). ACUITY major bleeding occurred in 3.0% and 5.7% of patients, respectively — a 47% relative risk reduction in favor of bivalirudin (p 75 It should be noted that the ACUITY trial used a different definition of major bleeding than other higher-risk NSTEMI trials. ACUITY bleeding included intracranial bleeding; intraocular bleeding; access-site hemorrhage requiring intervention; hematoma more than 5 cm in diameter; reduction in hemoglobin concentration of more than 4 g/dL without an overt source of bleeding; reduction in hemoglobin concentration of more than 3 g/dL with an overt source of bleeding; reoperation for bleeding and use of any blood-product transfusion.⁷⁵ Results from the ACUITY trial indicate that the direct thrombin inhibitor bivalirudin alone is “non inferior” to heparin or enoxaparin combined with a GP IIb/IIIa inhibitor in invasively managed patients with NSTE-ACS, with significantly less major bleeding.⁷⁶ The combination of bivalirudin with GP IIb/IIIa inhibitors was no better than the combination of heparin and GP IIb/IIIa inhibitors. Efficacy of bivalirudin in relation to clopidogrel. When the ACUITY study results were stratified by clopidogrel pretreatment there appeared to be an interaction with bivalirudin monotherapy.⁷⁵ The net clinical outcome, defined as a composite — death/MI/unplanned revascularization/major bleeding — in patients with and without prior clopidogrel is shown in Table 3. Bivalirudin monotherapy was associated with more ischemic events and worse net clinical outcomes than the IIb/IIIa arms in patients who had not received prior clopidogrel, while in those who had received clopidogrel there was no such difference. This raises concerns regarding the benefit of bivalirudin monotherapy in the absence of the potent antiplatelet effect of a GP IIb/IIIa antagonist or concomitant clopidogrel; this observation will need to be investigated further. Indirect Selective Xa Inhibitors Fondaparinux, a synthetic pentasaccharide, selectively binds antithrombin and causes rapid and predictable inhibition of factor Xa.⁷⁷ The OASIS-5 study assessed whether fondaparinux would preserve the anti-ischemic benefits of enoxaparin while reducing bleeding.⁶⁹ A total of 20,078 patients with ACS were randomly assigned to receive either fondaparinux (2.5 mg daily) or enoxaparin (1 mg/kg twice daily) for a mean of 6 days. The primary outcome was death, MI or refractory ischemia at 9 days.⁶⁹ The incidence of the primary endpoint was similar in both groups (5.8% for fondaparinux vs. 5.7% for enoxaparin). The rate of major bleeding was significantly lower among fondaparinux patients at 9 days (2.2% vs. 4.1%, respectively; p p p = 0.02) and 180 days (574 vs. 638, respectively; p = 0.05). The authors concluded that fondaparinux substantially reduces major bleeding and improves long-term morbidity and mortality.⁶⁹ This reduction in major bleeding, however, appears to be wholly related to vascular access site and retroperitoneal bleeding that very likely could be attributed to the stacking of “full dose UFH” on top of enoxaparin-treated patients who came to the catheterization laboratory beyond 6 hours after a full dose of enoxaparin. Panel Recommendations: Direct Thrombin and Indirect Xa Inhibitors Bivalirudin is a potentially useful alternative antithrombotic agent for PCI in low- and medium-plus risk NSTE-ACS patients which has significantly lower bleeding rates than the heparin/IIb/IIIa combination. The numerically higher rate of ischemic events with bivalirudin alone raises some concerns regarding its use in high risk patients, particularly in the absence of concomitant potent antiplatelet therapy. Fondaparinux may be useful as first line therapy for NSTE-ACS if the patient is not going to be managed with early catheterization. The need for additional UFH (in unknown doses) in fondaparinux-treated patients undergoing catheterization and PCI to prevent wire- and catheter-related thrombus makes it less attractive for invasively managed patients. Oral Platelet Antagonists Clopidogrel: Optimal timing of initiation. Based on the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) study,⁷⁸ the 2002 ACC/AHA Guidelines gave a Class I A recommendation for early loading (with 300 mgs), and administration of clopidogrel as part of the spectrum of care for patients with NSTE-ACS, in the absence of early CABG.⁴ However, there is evidence that clopidogrel is being underused, primarily because of concern about clopidogrel-related bleeding during CABG. Tricoci and colleagues studied 61,052 patients with high-risk NSTE-ACS (defined as the presence of positive cardiac markers and/or ischemic ST-segment changes), evaluating temporal trends of clopidogrel use at discharge since the ACC/AHA 2002 Guidelines update.⁷⁹ Only 34,319 patients (56.2%), received clopidogrel at discharge. While 96.3% of patients who underwent PCI received clopidogrel at discharge, only 42.8% of patients who did not undergo cardiac catheterization and 23.5% of the patients who underwent CABG went home on clopidogrel, even though they were admitted with high risk UA/NSTEMI.⁷⁹ Apart from PCI, variables favoring receiving clopidogrel at discharge included prior PCI, prior CABG, stroke, hypercholesterolemia, elevated cardiac markers compatible with an MI and inpatient care by a cardiologist. The authors concluded that while prescription of clopidogrel at hospital discharge in patients with NSTE-ACS who are treated with medical therapy alone and in those who undergo CABG has increased since release of the ACC/AHA Guidelines, most of these NSTE-ACS patients still do not receive clopidogrel at discharge.⁷⁹ Fox and colleagues examined the benefits and risks of early and long-term clopidogrel treatment among NSTE-ACS patients undergoing CABG and PCI enrolled in CURE.⁸⁰ They found that the reductions in CV death/nonfatal MI/stroke with early clopidogrel use were consistent among those undergoing PCI (9.6% for clopidogrel vs. 13.2% for placebo; RR = 0.72; 95% CI 0.57–0.90), CABG (14.5% for clopidogrel vs. 16.2% for placebo; RR = 0.89; 95% CI 0.71–1.11) and medical therapy only (8.1% for clopidogrel vs. 10.0% for placebo; RR = 0.80; 95% CI 0.69–0.92). For CABG during the initial hospitalization, the frequency of CV death, MI or stroke before CABG was 2.9% for clopidogrel vs. 4.7% for placebo (RR = 0.56; 95% CI 0.29–1.08).80 Among the total CURE population, there was a 1% excess of major bleeding, but no significant excess of life-threatening bleeding. Among patients undergoing CABG, the rates of life-threatening bleeding were 5.6% for clopidogrel and 4.2% for placebo (RR = 1.30; 95% CI 0.91–1.95; both nonsignificant). In fact, there was no increase in perioperative bleeding in those patients who were taken off clopidogrel for at least 5 days prior to CABG. Overall, the benefits of starting clopidogrel on admission appear to outweigh the risks, even among those who proceed to CABG during the initial hospitalization.⁸⁰ It should be emphasized that not all patients are appropriate candidates for early clopidogrel. Transfusions and life-threatening bleeds are increased by clopidogrel treatment in patients undergoing CABG within 5 days of their last dose of clopidogrel (OR = 1.50). Mehta et al has recently observed that a significant number of patients heading for CABG do not have clopidogrel discontinued and subsequently experience morbid bleeding events.⁸¹ More data supporting pretreatment with clopidogrel were provided by the Clopidogrel for Reduction of Events During Observation (CREDO) trial in patients undergoing PCI.⁸² The CREDO trial demonstrated that administration of a loading dose of clopidogrel 300 mg, prior to elective PCI, followed by 75 mg daily for 12 months, decreased the primary endpoint of death, MI or stroke by 27% in patients treated with clopidogrel for 1 year than in those treated for 1 month. Results were similar across multiple subgroups studied: in women and men, with and without ACS, with and without diabetes, as well as for patients who received GP IIb/IIIa inhibitors at the time of PCI and those who did not. While the primary endpoint measured at Day 28 was negative, there was a clear-cut trend by 28 days favoring pretreatment, particularly when clopidogrel was administered more than 6 hours before PCI.⁸²Clopidogrel: Optimal dose. The ACC/AHA/SCAI 2005 Percutaneous Coronary Intervention (PCI) Guideline Update states that in patients undergoing PCI and on a background of aspirin 325 mg daily, a loading dose of clopidogrel (300 mg) should be administered.⁸³ followed by clopidogrel 75 mg daily for at least 1 month after bare metal stent (BMS) implantation, or at least 3 months after sirolimus drug-eluting stent (DES) implantation, and 6 months after paclitaxel stent implantation, and ideally up to 12 months in patients who are not at high risk of bleeding.⁸³ However, issues have arisen concerning the optimal loading dose of clopidogrel used before PCI and about the safest duration of clopidogrel therapy after DES implantation. Hochholzer and colleagues evaluated the 600 mg clopidogrel loading dose in 1,001 patients who were scheduled for cardiac catheterization as potential candidates for PCI.⁸⁴ The authors measured platelet aggregation by optical aggregometry and surface expression of P-selectin and activated GP IIb/IIIa by flow cytometry. Platelet aggregation induced by 5 micromol/L ADP was 51 ± 14% when catheterization was performed within 1 hour; 41 ± 14% between 1 and 2 hours; 37 ± 15% between 2 and 4 hours; 36 ± 13% between 4 and 6 hours, and 35 ± 14% beyond 6 hours after clopidogrel administration. After 2 hours (n = 718), the level of platelet aggregation and the surface expression of P-selectin and activated GP IIb/IIIa did not change significantly with time after clopidogrel (p > 0.24 by univariate or multivariate regression).⁸⁴ Comedication with CYP3A4 metabolized statins did not significantly affect platelet aggregation after clopidogrel (p = 0.62). Among the 428 patients undergoing PCI, the 30-day composite rate of major adverse cardiac events was 1.9%, with no significant difference between patients undergoing PCI within 2 hours after clopidogrel loading and those undergoing PCI at a later time point. They concluded that after loading with 600 mg of clopidogrel, the full antiplatelet effect of the drug was achieved after 2 hours, and statins did not interfere with the level of platelet inhibition after this dose.⁸⁴ The Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty (ARMYDA-2) study evaluated 255 patients undergoing elective PCI who were randomized to a 600 mg (n = 126) or 300 mg (n = 129) loading regimen of clopidogrel given 4 to 8 hours before the procedure.⁸⁵ CK-MB, troponin I and myoglobin levels were measured at baseline and at 8 and 24 hours after intervention. The primary endpoint, death/MI/target vessel revascularization at Day 30, occurred in 4% of patients in the high loading dose versus 12% of those in the conventional loading dose group (p = 0.04) and was due entirely to periprocedural MI. Safety endpoints were similar in the two arms.⁸⁵ Higher loading doses than 600 mg have not shown major benefit as documented by the Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect (ISAR-CHOICE) trial. Sixty patients with suspected or documented CAD were allocated to one of three clopidogrel loading doses (300, 600 or 900 mg) in a double-blinded, randomized manner.86 Loading with 600 mg resulted in higher plasma concentrations of the active metabolite, compared with loading with 300 mg (p p = 0.01 and 0.004). With administration of 900 mg, no further increase in plasma concentrations of active metabolite, and no further suppression of adenosine diphosphate-induced platelet aggregation 4 hours after drug administration was achieved when compared with administration of 600 mg.⁸⁶ Clopidogrel responsiveness and post-treatment platelet aggregation were measured in patients undergoing stenting by Gurbel and colleagues in 190 patients randomly treated with either a 300 mg or a 600 mg clopidogrel load.⁸⁷ Both nonresponsiveness, defined as less than 10% absolute change in platelet aggregation post dose, and high posttreatment platelet aggregation, were lower after 600 mg compared to the 300 mg of clopidogrel (8% vs. 28%; p 87 Length of treatment after drug-eluting stent deployment. The Basel Stent Cost-effectiveness Trial — Late Thrombotic Events (BASKET-Late) study, presented at the 2006 ACC Annual Scientific Sessions included 743 patients with DES (either paclitaxel or sirolimus-eluting stents) or a bare-metal stent, in a 1:1:1 proportion.⁸⁸ The aim of the study was to evaluate late thrombotic events among patients treated with drug-eluting stents versus bare metal stents one year after discontinuation of clopidogrel. The study population comprised patients with STEMI (21%), UA (37%) and stable angina (42%). In the year following clopidogrel discontinuation, the primary composite endpoint of cardiac death or MI occurred significantly more frequently in the drug-eluting stent group (4.9% vs. 1.3%, respectively; p = 0.01). There was also a higher incidence of non-fatal MI in the drug-eluting stent group (4.1% vs. 1.3%, respectively; p = 0.04) and cardiac death trended higher (1.2% vs. 0%, respectively; p = 0.09). There were no differences in restenosis-driven target vessel revascularization (4.5% vs. 6.7%; p = 0.21). Late stent thrombosis (combination of angiographic document thrombosis and thrombotic clinical events) occurred in 2.6% of the drug-eluting stent group and 1.3% of the bare-metal stent group (p = 0.23).⁸⁸ The median time of the late thrombotic event was 116 days following clopidogrel discontinuation, but events occurred throughout the 1 year follow up (range 362 days). It remains unclear how long clopidogrel should be continued in the presence of DES, but most interventionalists are now continuing patients with DES for at least 1 year. The CREDO trial helped clarify the benefits and risks of adding a GP IIb/IIIa receptor antagonist during PCI to an antiplatelet regimen that included clopidogrel in those randomized to clopidogrel pretreatment. Compared with patients who received GP IIb/IIIa who were randomized to “no clopidogrel pretreatment,” those who received GP IIb/IIIa inhibitors and clopidogrel had a marked relative reduction in clinical events and no significant increase in major bleeding events.⁸²Panel Recommendations: Oral Platelet Inhibitors The decision to initiate clopidogrel therapy in the ED (prior to PCI), at the time of PCI (in the catheterization laboratory) or after PCI in patients with NSTE-ACS should be based on the physician’s best clinical assessment as to whether the patient is likely to need urgent CABG surgery (within 5 days). The Panel recommends that whenever possible, in patients who undergo PCI, clopidogrel should be administered as early as possible (based on current evidence at least 2 hours before PCI) prior to device activation, and a 600 mg load should be used. The Panel recommends the duration of clopidogrel therapy as follows: • BMS minimum 4 weeks (CURE-PCI and CREDO have shown benefit of prolonged administration up to 12 months) • SES minimum 3 months; (BASKET-LATE would suggest even a more prolonged administration possibly 12–14 months) • PES minimum 6 months; (BASKET-LATE would suggest even a more prolonged administration possibly 12–14 months) • Considering the available evidence of combined (dual) antiplatelet therapies in BMS plus DES, it is reasonable to extend therapy for a minimum of 12 months (if patient can tolerate/afford the regimen) Patient selection based on compliance with dual antiplatelet therapy, bleeding risk and possibility of surgical procedures in the foreseeable future can influence the choice of stent used during PCI. In patients with NSTE-ACS (positive troponin elevation) there is an incremental benefit of using triple antiplatelet therapy (ISAR-REACT 2: aspirin + clopidogrel 600/75 + abciximab). Clopidogrel, aspirin and warfarin: Some comments on “triple therapy.” In some patients with NSTE-ACS (those presenting on chronic oral anticoagulation with warfarin, as an example: prosthetic valve replacements or atrial fibrillation), the need for dual antiplatelet therapy (aspirin plus clopidogrel) and warfarin should be considered. There is limited peer-reviewed information and it is controversial. At least in the short term (30 days) it appears to be safe as documented by Porter and colleagues.⁸⁹ The authors sought to assess bleeding complications among patients undergoing PCI and receiving triple therapy of warfarin, aspirin and a thienopyridine. The study group included 180 patients [80% males; age 65 (52–75.5)]. PCI was used on an urgent/emergent basis in 86.6%. The main indications for warfarin use were LV mural thrombus and atrial fibrillation (46.9 and 36.9%, respectively).⁸⁹ Post-PCI triple therapy duration was 30 days. During the post-triple therapy, 104 patients (57.8%) continued treatment with warfarin and aspirin for 376 days (150–775). During the triple therapy period, 20 patients developed bleeding complications, [mean INR 2.1 ± 0.7 at 7 (6–8.5) days post-PCI): 2 major groin hematomas (initial phase of warfarin treatment during overlap with heparin) and 18 minor. During post-triple therapy, primarily under warfarin and aspirin, 19 patients developed bleeding complications: 1 major and 18 minor. The authors conclude that short-term triple therapy after PCI was not associated with prohibitively high bleeding complication rates, and thus should be favorably considered in patients with a clear indication for warfarin use.⁸⁹ However, other groups have shown the opposite. Khurram and colleagues evaluated the bleeding risk in patients requiring chronic warfarin therapy and undergoing stent implantation.⁹⁰ They compared 107 consecutive patients on chronic warfarin therapy who underwent coronary stenting and were discharged on aspirin, clopidogrel and warfarin, with 107 contemporary patients who were treated with aspirin and clopidogrel. Major bleeding was defined as bleeding that was significantly disabling, intraocular or requiring at least 2 units of blood transfusion. Minor bleeding was defined as other bleeding that led to interruption of the medications. Patients on triple therapy were younger and more likely to have hypertension. This group had significantly higher major bleeding (6.6% vs. 0%; p = 0.03) and minor bleeding (14.9% vs. 3.8%; p = 0.01) compared with the dual antiplatelet therapy group.90 In the triple therapy group, the INR or aspirin dosage did not influence the bleeding risk. In patients requiring warfarin therapy, the addition of dual antiplatelet therapy was associated with an approximately 7% major bleeding risk.⁹⁰ Appropriate risk/benefit evaluation is recommended in this setting of triple oral therapy. Emerging platelet inhibitor therapies. There are a number of novel antithrombotic agents currently being investigated for use in NSTE-ACS. Among these is prasugrel, a potent thienopyridine P2Y-12 receptor antagonist believed to have the potential to achieve higher levels of inhibition of ADP-induced platelet aggregation than currently approved doses of clopidogrel (300 mg load).⁹¹ The Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial was a phase 2, randomized, dose-ranging, double-blind safety trial of prasugrel versus clopidogrel in 904 patients undergoing elective or urgent PCI. No significant differences between patients treated with prasugrel or clopidogrel were observed in the rate of significant bleeding (1.7% vs. 1.2%, respectively). In prasugrel-treated patients, there was a nonsignificant lower incidence of the 30-day major adverse cardiac events and of MI, recurrent ischemia and clinical target vessel thrombosis.⁹¹ A Phase III clinical study with prasugrel is ongoing in ACS patients undergoing PCI — the TRITON-TIMI-38 study. Results from substudies of the Dose confirmation Study assessing anti-Platelet Effects of AZD6140 versus clopidogrel in NSTEMI-2 (DISPERSE 2) study were presented at the 2006 ACC annual meeting. AZD6140 is a reversible oral ADP-receptor antagonist for ACS. DISPERSE 2 was a double-blind, double-dummy, parallel group, randomized dose confirmation and feasibility study of AZD6140 plus ASA versus clopidogrel plus aspirin in 990 patients with NSTE-ACS.^92,93 On Day 1, at two hours after the first dose, the mean inhibition of platelet aggregation (IPA) was 66% for the AZD6140 90 mg group, 80% for the AZD6140 180 mg group, and 82% for the AZD6140 270 mg group versus 22% for the clopidogrel 300 mg group.⁹³ The second substudy, involving 44 patients assessed the effect on platelets of administering AZD6140 in patients who received clopidogrel prior to entry into the study.⁹⁴ The primary measure of this substudy was final platelet aggregation as measured prior to study drug dosing and at 2, 4, 8 and 12 hours after AZD6140 or clopidogrel administration on Day 1. Mean platelet aggregation prior to dosing was AZD6140 90 mg 48%, AZD6140 180 mg 34%, AZD6140 270 mg 43%, and clopidogrel 75 mg 38%. In the clopidogrel-only group, the mean decrease in platelet aggregation across time points ranged from 2% to 11%, while the mean decrease was 37% to 38% for the AZD6140 90 mg group, 28% to 32% for the AZD6140 180 mg group, and 34% to 42% for the AZD6140 270 mg group.⁹⁴ In conclusion: different doses of AZD6140 twice daily were well tolerated and quite efficacious with regard to antiplatelet efficacy. AZD6140 is being further studied in a large-scale head-to-head study versus clopidogrel. The Phase III clinical trial for AZD6140, PLATO (A Study of Platelet Inhibition and Patient Outcomes), which will commence in 2006. PLATO is a head-to-head outcomes study of AZD6140 versus clopidogrel being conducted in 40 countries through 1,000 investigational centers and will include 16,000 ACS patients. Intravenous Platelet Inhibitors GP IIb/IIIa receptor antagonists. Currently, therapy with a GP IIb/IIIa antagonist for NSTE-ACS patients without high-risk triggers is not supported by evidence-based trials.⁹⁵ In particular, the use of abciximab in patients being managed without revascularization may be associated with inferior outcomes. These observations are from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-IV) acute coronary syndrome trial,⁹⁵ and a detailed evaluation of medical therapy in previously reported GP IIb/IIIa agent trials. The GUSTO-IV trial enrolled 7,800 patients, all of whom received aspirin and a heparin compound, and were randomized to one of three arms (placebo, an abciximab bolus and 24-hour infusion, or an abciximab bolus and 48-hour infusion).⁹⁵ At 30 days, the composite of death or MI ranged from 8.0% to 9.1%, with no differences among the three treatment groups. At 48 hours, death occurred more commonly in the 48-hour abciximab group than in the placebo group (0.3% vs. 0.9%; p = 0.008). The lack of benefit of abciximab was observed in most subgroups, including high-risk patients as defined by an increased concentration of troponin.⁹⁵ Based on the above⁹⁵ and the results of the PURSUIT^96,97 study, patients with high-risk NSTE-ACS should receive a small-molecule GP IIb/IIIa inhibitor. Although the data supporting the use of GP IIb/IIIa antagonists are clearly stronger in patients undergoing early revascularization, patients with high-risk features who are being managed medically also benefit from the addition of a GP IIb/IIIa antagonist, although the degree of benefit is less marked.¹⁴ Emergency physicians and noninterventional cardiologists should initiate therapy with a small-molecule GP IIb/IIIa antagonist such as eptifibatide when the NSTE-ACS patient manifests high-risk features, even when the timing of intervention is uncertain. The ACC/AHA guidelines advocate the use of GP IIb/IIIa antagonists in all patients referred for PCI in the setting of UA/NSTEMI (Class I: level of evidence A). Support for early administration of eptifibatide in high-risk ACS patients managed with either an interventional strategy or because cardiac catheterization facilities were not available and/or transfer was not feasible (an alternative medical approach) is derived primarily from the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT)-U.S. study.⁹⁶ PURSUIT was a multinational, randomized, placebo-controlled trial which demonstrated that eptifibatide reduced the incidence of death or MI among patients with acute ischemic syndromes without ST-segment elevation. Because of differences in practice patterns among participating countries, a prospectively planned analysis of outcomes by regions of the world was performed. The PURSUIT-U.S. subset analysis provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the U.S. Eptifibatide reduced the primary endpoint of death or MI to 30 days from 15.4% to 11.9% (p = 0.003) among patients in the U.S.⁹⁶ The treatment effect was achieved early and maintained over a period of 6 months (18.9% vs. 15.2%; p = 0.004). Bleeding events were more common in patients receiving eptifibatide, but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the U.S. than elsewhere in the world.⁹⁶ The clinical benefit of eptifibatide was observed early (within the first 96 hours) and was maintained without attenuation after discontinuation of study drug. The absolute number of events (death or MI) prevented per 100 patients treated was 3.2 at 96 hours, 3.0 at 7 days, 3.5 at 30 days and 3.7 at 6 months.⁹⁶ Eptifibatide benefit was gender-independent, with both men and women in the U.S. having comparable clinical benefit. One investigative group performed a meta-analysis of the effect of medical therapy with GP IIb/IIIa agents from all six large, randomized, placebo-controlled trials (including the GUSTO-IV ACS trial) involving 31,402 patients with NSTE-ACS not routinely scheduled to undergo coronary revascularization.⁹⁷ A significant reduction in the likelihood of the composite endpoint of death or MI was demonstrated in the GP IIb/IIIa treatment arm (11.8% vs. 10.8%; OR = 0.91; 95% CI 0.84–0.98; p = 0.015). Although not scheduled for coronary revascularization procedures, a total of 11,965 of the 31,402 patients (38%) actually underwent PCI or CABG within 30 days; in this late interventional subgroup, the OR for death or MI in the treated patients was 0.89 (95% CI 0.80–0.98). In the 19,416 patients in this analysis who did not undergo PCI or CABG, the OR for death or MI in the GP IIb/IIIa group was 0.95 (95% CI 0.86–1.05; p = NS).⁹⁷ Major bleeding complications were significantly more common in the GP IIb/IIIa group compared with those in the placebo group (2.4% vs. 1.4%; p n = 120) who were enrolled in a 2 x 2 factorial study (300 mg clopidogrel with or without eptifibatide; 600 mg clopidogrel with or without eptifibatide).⁹⁸ Clopidogrel was administered immediately after stenting. Aggregometry and flow cytometry were used to assess platelet reactivity. Eptifibatide added a greater than or equal to two-fold increase in platelet inhibition to 600 mg clopidogrel alone at 3, 8, and 18 to 24 hours after stenting as measured by 5 mmol/l ADP-induced aggregation (p p p 98 Currently, GP IIb/IIIa inhibitors are the only class of agents proven to reduce the long-term incidence of MI and mortality in the setting of PCI. One group examined data from five trials that included more than 5,000 patients with stent implantation.⁹⁹ In this analysis, the standard use of GP IIb/IIIa inhibitors during PCI plus stenting prevented 11 deaths for every 1,000 patients treated.⁹⁹ In the setting of elective stenting without clopidogrel pretreatment, the use of a GP IIb/IIIa inhibitor produces superior platelet inhibition and lower myocardial necrosis compared with high-dose (600 mg) or standard-dose (300 mg) clopidogrel loading alone. In the absence of a GP IIb/IIIa inhibitor, 600 mg clopidogrel provides better platelet inhibition than the standard 300 mg dose.⁹⁸ To compare dual (aspirin + clopidogrel) versus triple antiplatelet (aspirin + clopidogrel + IIb/IIIa inhibition) pretreatment in patients with NSTE-ACS, Rasoul and colleagues evaluated in the Early or Late Intervention in Unstable Angina (ELISA)-2 trial a total of 328 consecutive patients.¹⁰⁰ They were randomized to pretreatment with dual (n = 166, aspirin, clopidogrel 600 mg) or triple antiplatelet therapy (n = 162, aspirin, clopidogrel 300 mg and aggrastat). The primary endpoint was enzymatic infarct size, defined as cumulative LDH release. Initial TIMI flow of the culprit vessel was a prespecified secondary endpoint.⁹⁹ Angiography was performed in 98% of patients at a median of 23 hours after admission. Enzymatic infarct size (median, 25–75%) was 166 (60–349) IU/l in the triple group compared with 193 (75–466) IU/l in the dual group (p = 0.2). Initial TIMI 3 flow of the culprit vessel was significantly more often observed after triple antiplatelet therapy (67 vs. 47%, p = 0.002). At 30-day follow up, MI occurred in 46% of patients in the triple antiplatelet group compared with 57% in the dual antiplatelet group (p = 0.052).¹⁰⁰ No significant difference in bleeding was present. This study showed that in patients with NSTE-ACS, triple antiplatelet pretreatment was associated with a nonsignificant reduction in enzymatic infarct size, a significantly better initial perfusion of the culprit vessel and a trend towards a better survival rate without death or MI.¹⁰⁰ A more recent study, the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Actions for Coronary Treatment-2 (ISAR-REACT 2) trial, assessed whether or not abciximab is associated with clinical benefit in high-risk patients with ACS undergoing PCI after pretreatment with 600 mg of clopidogrel.¹⁰¹ Patients were randomized to receive either abciximab [0.25 mg/kg bolus, followed by a 0.125 µg/kg per minute (maximum 10 µg/minute)] for 12 hours or placebo (placebo bolus and infusion for 12 hours plus heparin bolus 140 U/kg). All patients received clopidogrel 600 mg at least 2 hours prior to the procedure, as well as 500 mg of oral or intravenous aspirin.¹⁰¹ The primary endpoint was a composite of death, MI or urgent target vessel revascularization occurring within 30 days after randomization. Abciximab resulted in a 25% reduction in the primary endpoint compared with placebo (8.9% vs. 11.9%, respectively; p = 0.03) in the population as a whole and a significant reduction in the incidence of events among patients with an elevated troponin level (p = 0.2).¹⁰¹ There were not significant differences between the groups in the risk of major and minor bleeding and need for transfusion. The recently published PROTECT-TIMI-30 trial evaluated GP IIb/IIIa inhibition with eptifibatide when administered with indirect thrombin inhibition compared with monotherapy with direct thrombin inhibition with bivalirudin in patients with NSTE-ACS.¹⁰² Patients were randomized to either eptifibatide plus reduced-dose UFH, eptifibatide plus reduced-dose enoxaparin or bivalirudin monotherapy. Among angiographically evaluable patients, the primary endpoint of post-PCI coronary flow reserve was significantly higher with bivalirudin alone than the pooled eptifibatide arms (p = 0.036). A greater proportion of patients in the eptifibatide arms had normal TIMI myocardial perfusion compared with bivalirudin (57.9% vs. 50.9%, respectively; p = 0.048). In addition, the duration of ischemia as measured by continuous Holter monitoring following PCI was significantly longer among bivalirudin-treated patients (169 minutes vs. 36 minutes, respectively; p = 0.013).¹⁰² There were no significant differences in TIMI major bleeding between eptifibatide and bivalirudin; however, significantly more eptifibatide-treated patients had minor bleeding (2.5% vs. 0,4%, respectively; p = 0.027) and transfusions (4.4% vs. 0.4%, respectively; p 102 Panel Recommendations: GP IIb/IIIa Inhibitors All high-risk UA/NSTEMI, as recently reempasized by Puma et al,¹⁰³ should be considered for GP IIb/IIIa inhibition with a small molecule such as eptifibatide based on current ACC/AHA guidelines. The dose of eptifibatide should be very carefully adjusted for renal function, especially in the elderly and in women, as supported by the recent analyses by Kirtane et al¹⁰⁴ and Alexander et al.¹⁰⁵Summary of CATH Panel Recommendations (Figure 7) Our goal is to improve clinical outcomes by abiding with evidence based-medicine and guidelines. A recent study by Peterson and colleagues demonstrates that adherence to guidelines does make a difference in outcomes.¹⁰⁶ Hospitals were divided into quartiles according to their adherence to composite adherence scores (i.e., total score for adherence to individual recommendations). Figure 8 shows risk-adjusted mortality rates for NSTEMI-ACS as a function of composite guideline adherence for participating hospitals.¹⁰⁶ It is clear that hospitals with a higher level of adherence to guidelines have lower mortality rates. The goals for the management of NSTE-ACS patients are rapid and accurate risk stratification, appropriate and institution-specific triage to interventional versus medical strategies and optimal pharmacologic therapy — all of which provide for a smooth and seamless transition of care between the ED and the cardiology service. High-risk features or absolute treatment trigger criteria that support more aggressive medical therapy (i.e., addition of small molecule GP IIb/IIIa inhibitor to a core regimen of aspirin, enoxaparin, and in most cases, clopidogrel) and/or that would direct clinicians toward percutaneous, mechanical/interventional strategies as the preferred modality include, but are not limited to, the presence of one or more of the following: (1) elevated cardiac markers (troponin and/or CK-MB); (2) elevated levels of inflammatory markers (particularly CRP > 3 µg/dl); (3) age older than 65 years; (4) presence of ST-T wave changes; (5) TIMI Risk Score greater than or equal to 4; (6) diabetes; and/or 7) clinical instability in the setting of suspected NSTE-ACS. Increased emphasis has been placed on the concept that pharmacological and interventional strategies should be risk-directed. In this vein, a hierarchical approach to ACS management in which pharmacological and mechanical modalities are pressed into service according to a “sliding scale”. In this model, specific clinical, ECG and/or biochemical trigger points modulate the aggressiveness of both the medical therapy and the propensity to perform early angiography with or without subsequent revascularization patients with ACS (see Appendix). Although additional refinements and changes in ACS management are still to come, evidence-based strategies suggest that prompt mechanical revascularization is associated with the best possible clinical outcomes, particularly for patients with high-risk features and in whom benefits of adjunctive, pharmacoinvasive antithrombotic therapies can be consolidated. Patient transfer for cardiac catheterization/PCI is strongly recommended in patients who manifest high-risk features and/or aggressive treatment trigger criteria, so that this high-risk subgroup may receive definitive interventional and/or cardiology-directed specialty care at appropriate sites of care. When available, interventional management is preferred in these patients. The importance of safe and effective anticoagulation in the spectrum of management strategies has been confirmed, and the evidence in support of enoxaparin and other antithrombotic agents has been reviewed. Dosing recommendations for enoxaparin use in the setting of PCI have been issued by the CATH Panel and have been summarized in this consensus report. Similar recommendations have been presented for the use of oral antiplatelet agents and GP IIb/IIIa antagonists. The addition of statins, ACE inhibitors and beta-blockers is also stressed as part of a comprehensive secondary cardioprotective strategy for patients with coronary heart disease.

References 1. Gibler WB, Cannon CP, Blomkalns AL, et al. Practical implementation of the guidelines for unstable angina/non-ST-segment elevation myocardial infarction in the emergency department: A scientific statement from the American Heart Association Council on Clinical Cardiology (Subcommittee on Acute Cardiac Care), Council on Cardiovascular Nursing, and Quality of Care and Outcomes Research Interdisciplinary Working Group, in Collaboration With the Society of Chest Pain Centers. Circulation 2005;111:2699–2710. 2. Armstrong PW, Fu Y, Chang WC, et al. Acute coronary syndromes in the GUSTO-IIb trial: prognostic insights and impact of recurrent ischemia. The GUSTO-IIb Investigators. Circulation 1998;98:1860–1868. 3. Steg PG, Goldberg RJ, Gore JM, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). Am J Cardiol 2002;90:358–363. 4. 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;40:1366–1374. 5. Q1 2006 CRUSADE data. Duke Clinical Research Institute, 2003. 6. Alexander KP, Chen AY, Roe MT, et al. Excess dosing of antiplatelet and antithrombin agents in the treatment of non-ST-segment elevation acute coronary syndromes. JAMA 2005;294:3108–3116. 7. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114:774–782. 8. Rao SV, O’Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:809–816. 9. Yang X, Alexander KP, Chen AY, et al. The implications of blood transfusions for patients with non-ST-segment elevation acute coronary syndromes: Results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol 2005;46:1490–1495. 10. Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000;284:835–842. 11. Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation 1999;100:1593–1601. 12. Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. N Engl J Med 1997;337:447–452. 13. Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879–1887. 14. 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;338:1488–1497. 15. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998;339:436–443. 16. James SK, Lindahl B, Siegbahn A, et al. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: A Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation 2003;108:275–281. 17. Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation 2002;105:1760–1763. 18. Jaffe AS, Babuin L, Apple FS. Biomarkers in acute cardiac disease: The present and the future. J Am Coll Cardiol 2006;48:1–11. 19. Moscucci M, Fox KA, Cannon CP, et al. Predictors of major bleeding in acute coronary syndromes: The Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1815–1823. 20. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555–1562. 21. Sabatine MS, Morrow DA, Giugliano RP, et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation 2005;111:2042–2049. 22. Wu WC, Rathore SS, Wang Y, et al. Blood transfusion in elderly patients with acute myocardial infarction. N Engl J Med 2001;345:1230–1236. 23. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92:930–935. 24. Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol 2005;96:1200–1206. 25. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO investigators. N Engl J Med 1993;329:673–682. 26. Chesebro JH, Knatterud G, Roberts R, et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: A comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76:142–154. 27. Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: Primary results of the SYNERGY randomized trial. JAMA 2004;292:45–54. 28. Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction. Results of the TIMI IIIB Trial. Thrombolysis in Myocardial Ischemia. Circulation 1994;89:1545–1556. 29. Boden WE, O’Rourke RA, Crawford MH, et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. Veterans Affairs Non-Q-Wave Infarction Strategies in Hospital (VANQWISH) Trial Investigators. N Engl J Med 1998;338:1785–1792. 30. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators. Lancet 1999;354:708–715. 31. Fox KA, Poole-Wilson PA, Henderson RA, et al. Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: The British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina. Lancet 2002;360:743-751. 32. Lagerqvist B, Husted S, Kontny F, et al. A long-term perspective on the protective effects of an early invasive strategy in unstable coronary artery disease: Two-year follow-up of the FRISC-II invasive study. J Am Coll Cardiol 2002;40:1902–1914. 33. Morrow DA, Cannon CP, Rifai, et al. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: Results from a randomized trial. JAMA 2001;286:2405–2412. 34. Glaser R, Herrmann HC, Murphy SA, et al. Benefit of an early invasive management strategy in women with acute coronary syndromes. JAMA 2002;288:3124–3129. 35. Bach RG, Cannon CP, Weintraub WS, et al. The effect of routine, early invasive management on outcome for elderly patients with non-ST-segment elevation acute coronary syndromes. Ann Intern Med 2004;141:186–195. 36. Mahoney EM, Jurkovitz CT, Chu H, et al. Cost and cost-effectiveness of an early invasive versus conservative strategy for the treatment of unstable angina and non-ST-segment elevation myocardial infarction. JAMA 2002;288:1851–1858. 37. Fox KA, Poole-Wilson P, Clayton TC, et al. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: The British Heart Foundation RITA 3 randomised trial. Lancet 2005;366:914–920. 38. Yusuf S, Zucker D, Peduzzi P, et al. Effect of coronary artery bypass graft surgery on survival: overview of 10-year results from randomised trials by the Coronary Artery Bypass Graft Surgery Trialists Collaboration. Lancet 1994;344:563–570. 39. de Winter RJ, Windhausen F, Cornel JH, et al. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med 2005;353:1095–1104. 40. Neumann FJ, Kastrati A, Pogatsa-Murray G, et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: A randomized controlled trial. JAMA 2003;290:1593–1599. 41. Spacek R, Widimsky P, Straka Z, et al. Value of first day angiography/angioplasty in evolving Non-ST segment elevation myocardial infarction: An open multicenter randomized trial. The VINO Study. Eur Heart J 2002;23:230–238. 42. Hoenig MR. Cochrane Database of Systematic Reviews 2006:Art. 3 No:CD004815. DOI:10.1002/14651858.CD004815.pub2. 43. Mehta SR, Cannon CP, Fox KA, et al. Routine versus selective invasive strategies in patients with acute coronary syndromes: A collaborative meta-analysis of randomized trials. JAMA 2005;293:2908–2917. 44. Budaj A, Brieger D, Steg PG, et al. Global patterns of use of antithrombotic and antiplatelet therapies in patients with acute coronary syndromes: Insights from the Global Registry of Acute Coronary Events (GRACE). Am Heart J 2003;146:999–1006. 45. Singh KP, Roe MT, Peterson ED, et al. Low-molecular-weight heparin compared with unfractionated heparin for patients with non-ST-segment elevation acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors: Results from the CRUSADE initiative. J Thromb Thrombolysis 2006;21:211–220. 46. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: The ASSENT-3 randomised trial in acute myocardial infarction. Lancet 2001;358:605–613. 47. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477–1488. 48. Bijsterveld NR, Moons AH, Meijers JC, et al. The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular-weight heparin in the initial treatment of acute coronary syndromes. J Am Coll Cardiol 2003;42:424–427. 49. Hirsh J, Raschke R. Heparin and low-molecular-weight heparin: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:188S–203S. 50. Collet JP, Montalescot G, Lison L, et al. Percutaneous coronary intervention after subcutaneous enoxaparin pretreatment in patients with unstable angina pectoris. Circulation 2001;103:658–663. 51. Martin JL, Fry ETA, Sanderink GJ, et al. Reliable anticoagulation with enoxaparin in patients undergoing percutaneous coronary intervention: The pharmacokinetics of enoxaparin in PCI (PEPCI) study. Catheter Cardiovasc Interv 2004;61:163–70. 52. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006–1017. 53. Klein W, Buchwald A, Hillis SE, et al. Comparison of low-molecular-weight heparin with unfractionated heparin acutely and with placebo for 6 weeks in the management of unstable coronary artery disease. Fragmin in unstable coronary artery disease study (FRIC). Circulation 1997;96:61–68. 54. Comparison of two treatment durations (6 days and 14 days) of a low molecular weight heparin with a 6-day treatment of unfractionated heparin in the initial management of unstable angina or non-Q wave myocardial infarction: FRAX.I.S. (FRAxiparine in Ischaemic Syndrome). Eur Heart J 1999;20:1553–1562. 55. Eikelboom JW, Anand SS, Malmberg K, et al. Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: A meta-analysis. Lancet 2000;355:1936–1942. 56. Kaul S, Shah PK. Low molecular weight heparin in acute coronary syndrome: Evidence for superior or equivalent efficacy compared with unfractionated heparin? J Am Coll Cardiol 2000;35:1699–1712. 57. Michalis LK, Katsouras CS, Papamichael N, et al. Enoxaparin versus tinzaparin in non-ST-segment elevation acute coronary syndromes: The EVET trial. Am Heart J 2003;146:304–310. 58. Faxon DP, Spiro TE, Minor S, et al. Low molecular weight heparin in prevention of restenosis after angioplasty. Results of Enoxaparin Restenosis (ERA) Trial. Circulation 1994;90:908–914. 59. Karsch KR, Preisack MB, Baildon R, et al. Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-blind Unfractionated heparin and placebo-controlled Evaluation. J Am Coll Cardiol 1996;28:1437–1443. 60. Diez JG, Lievano, MJ, Croitoru M, et al. Enoxaparin anticoagulation for percutaneous coronary interventions. A pilot safety study. Circulation 1999;18:1–188. 61. Rabah MM, Premmereur J, Graham M, et al. Usefulness of intravenous enoxaparin for percutaneous coronary intervention in stable angina pectoris. Am J Cardiol 1999;84:1391–1395. 62. Kereiakes DJ, Grines C, Fry E, et al. Enoxaparin and abciximab adjunctive pharmacotherapy during percutaneous coronary intervention. J Invasive Cardiol 2001;13:272–278. 63. Bhatt DL, Lee BI, Casterella PJ, et al. Safety of concomitant therapy with eptifibatide and enoxaparin in patients undergoing percutaneous coronary intervention: Results of the Coronary Revascularization Using Integrilin and Single bolus Enoxaparin Study. J Am Coll Cardiol 2003;41:20–25. 64. Choussat R, Montalescot G, Collet JP, et al. A unique, low dose of intravenous enoxaparin in elective percutaneous coronary intervention. J Am Coll Cardiol 2002;40:1943–1950. 65. Borentain M, Montalescot G, Bouzamondo A, et al. Low-molecular-weight heparin versus unfractionated heparin in percutaneous coronary intervention: A combined analysis. Catheter Cardiovasc Interv 2005;65:212–221. 66. Ferguson JJ, Antman EM, Bates ER, et al. Combining enoxaparin and glycoprotein IIb/IIIa antagonists for the treatment of acute coronary syndromes: Final results of the National Investigators Collaborating on Enoxaparin-3 (NICE-3) study. Am Heart J 2003;146:628–634. 67. Blazing MA, de Lemos JA, White HD, et al. Safety and efficacy of enoxaparin versus unfractionated heparin in patients with non-ST-segment elevation acute coronary syndromes who receive tirofiban and aspirin: A randomized controlled trial. JAMA 2004;292:55–64. 68. Cohen M, Mahaffey KW, Pieper K, et al. A subgroup of analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial. J Am Coll Cardiol 2006 (in press). 69. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med 2006;354:1464–1476. 70. Gibson M. PCI-ExTRACT-TIMI 25. Percutaneous coronary intervention outcomes anong patients treated with enoxaparin versus unfractionated heparin following fibrinolytic administration for ST-elevation myocardial infarction in the EXTRACT-TIMI 25 investigators, World Congress of Cardiology 2006, Barcelona, Spain, Sept 2–6, 2006. 71. Petersen JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-Segment elevation acute coronary syndromes: A systematic overview. JAMA 2004;292:89–96. 72. Greenbaum AB, Harrington RA, Hudson MP, et al. Therapeutic value of eptifibatide at community hospitals transferring patients to tertiary referral centers early after admission for acute coronary syndromes. PURSUIT Investigators. J Am Coll Cardiol 2001;37:492–498. 73. Goodman SG, Fitchett D, Armstrong PW, et al. Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation 2003;107:238–244. 74. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853–863. 75. Stone GW, McLaurin BT, Ware JH, et al. Prospective, randomized comparison of heparin plus IIb/IIIa inhibition and bivalirudin with or without IIb/IIIa inhibition in patients with acute coronary syndromes: The ACUITY Trial, American College of Cardiology 55th Annual Scientific Sessions, Atlanta, Georgia, March 11–14, 2006. 76. Kaul S, Shah PK, Diamond GA. Bivalirudin during early invasive strategy for acute coronary syndromes: Non-inferiority in ACUITY lies in the eyes of the beholder. Circulation 2006;114:(Suppl II):II–552. 77. Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001; 119:95S–107S. 78. Yusuf S, Zhao F, Mehta SR, et al. 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. 79. Tricoci P, Roe MT, Mulgund J, et al. Clopidogrel to treat patients with non-ST-segment elevation acute coronary syndromes after hospital discharge. Arch Intern Med 2006;166:806–811. 80. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome: The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110:1202–1208. 81. Mehta RH, Roe MT, Mulgund J, et al. Acute clopidogrel use and outcomes in patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass surgery. J Am Coll Cardiol 2006;48:281–286. 82. Steinhubl SR, Berger PB, Mann JT 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: A randomized controlled trial. JAMA 2002;288:2411–2420. 83. Smith SC Jr, Feldman TE, Hirshfeld JW Jr, et al. ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention—Summary article: 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). Circulation 2006;113:156–175. 84. Hochholzer W, Trenk D, Frundi D, et al. Time dependence of platelet inhibition after a 600-mg loading dose of clopidogrel in a large, unselected cohort of candidates for percutaneous coronary intervention. Circulation 2005;111:2560–2564. 85. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005;111:2099–2106. 86. von Beckerath N, Taubert D, Pogatsa-Murray G, et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) trial. Circulation 2005;112:2946–2950. 87. Gurbel PA, Bliden KP, Hayes KM, et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005;45:1392–1396. 88. Pfisterer ME, Kaiser CA, Bader F, et al. Late clinical events related to late stent thrombosis after stopping clopidogrel: Prospective randomized comparison between drug-eluting stents versus bare-metal stenting, American College of Cardiology 55th Annual Scientific Sessions, Atlanta, Georgia, March 11–14, 2006. 89. Porter A, Konstantino Y, Iakobishvili Z, et al. Short-term triple therapy with aspirin, warfarin, and a thienopyridine among patients undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv 2006;68:56–61. 90. Khurram Z, Chou E, Minutello R, et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J Invasive Cardiol 2006;18:162–164. 91. Wiviott SD, Antman EM, Winters KJ, et al. Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: Results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation 2005;111:3366–3373. 92. Cannon CP, Husted S, Storey RF, et al. Safety, tolerability, and preliminary efficacy of AZD6140, the first oral reversible ADP receptor antagonist compared with clopidogrel in patients with non-ST segment elevation acute coronary syndrome (The DISPERSE2 Study), American Heart Association Scientific Sessions 2005, Dallas, Texas, November 13–16, 2006. 93. Storey R, Husted S, Harrington RA, et al. AZD6140 yields greater inhibition of platelet aggregation than clopidogrel in patients with acute coronary syndromes without previous clopidogrel treatment, American College of Cardiology 55th Annual Scientific Sessions, Atlanta, Georgia, March 11–14, 2006. 94. Storey R, Harrington RA, Husted S, et al. AZD6140 yields additional suppression of platelet aggregation in patients with acute coronary syndromes previously treated with clopidogrel, American College of Cardiology 55th Annual Scientific Sessions, Atlanta, Georgia, March 11–14, 2006. 95. Simoons ML. 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;357:1915–1924. 96. Lincoff AM, Harrington RA, Califf RM, et al. Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition. Insights from the platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial. Circulation 2000;102:1093–1100. 97. Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: A meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–198. 98. Gurbel PA, Bliden KP, Zaman KA, et al. 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;111:1153–1159. 99. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: Emerging platelet preeminence. Circulation 1998;97:211–218. 100. Rasoul S, Ottervanger JP, de Boer MJ, et al. A comparison of dual versus triple antiplatelet therapy in patients with non-ST-segment elevation acute coronary syndrome: Results of the ELISA-2 trial. Eur Heart J 2006;27:1401–1407. 101. Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA 2006;295:1531–1538. 102. Gibson CM, Morrow DA, Murphy SA, et al. A randomized trial to evaluate the relative protection against post-percutaneous coronary intervention microvascular dysfunction, ischemia, and inflammation among antiplatelet and antithrombotic agents: The PROTECT-TIMI-30 trial. J Am Coll Cardiol 2006;47:2364–2373. 103. Puma JA, Banko LT, Pieper KS, et al. Clinical characteristics predict benefits from eptifibatide therapy during coronary stenting. Insights from the enhanced suppression of the platelet IIb/IIIa receptor with integrilin Therapy (ESPRIT) Trial. J Am Coll Cardiol 2006;47:715–718. 104. Kirtane AJ, Piazza G, Murphy SA, et al. for the TIMI Study Group. Correlates of bleeding events among moderate- to high-risk patients undergoing percutaneous coronary intervention and treated with eptifibatide: observations from the PROTECT-TIMI-30 trial. J Am Coll Cardiol. 2006;47:2374–2379. 105. Alexander KP, Chen AY, Newby LK, et al. Sex differences in major bleeding with glycoprotein IIb/IIIa inhibitors: Results from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early implementation of the ACC/AHA Guidelines) initiative. Circulation 2006;114;1380–1387. 106. Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA 2006;295:1912–1920.