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

A total of 5,225 patients were enrolled in the PARAGON B trial. Among these patients, the type of heparin used was known in 5,200 (99.5%). The median duration of therapy was 72.8 hours for UFH and 79.7 hours for LMWH. LMWH was used in about one-fifth of the study cohort. Of the 389 sites that participated, approximately 61% of the sites used UFH only, 10% used LMWH only, and 28% used either UFH or LMWH (at the discretion of the attending physician). Enoxaparin was used in 91% of the patients treated with LMWH.36 In the PARAGON B trial, use of the LMWH enoxaparin in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. The lower event rate for patients managed with LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% versus 42.8%) and a lower composite rate of death/MI (13.8% versus 11.9%). Bleeding was comparable in the 2 groups (1.4% with UFH versus 0.9% with LMWH). The propensity adjusted OR for 30-day revascularization was significantly lower with LMWH (OR, 0.67; 95% CI, 0.57–0.79; p 4), whether they underwent PCI (OR, 0.60; 95% CI, 0.35–1.01) or not (OR, 0.69; 95% CI, 0.49–0.99).1,46 However, no apparent benefit was observed in patients who were at lower risk.46 Based on this and other studies, patients with high-risk 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, NSTEMI 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.47 Emergency physicians and non-interventional 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. 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 PURSUIT-United States (US) study.48 PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) 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-US subset analysis provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States. Of the 10,948 patients randomized worldwide, a total of 4,035 were enrolled within the US. Patients were allocated to placebo or eptifibatide infusion for 72–96 hours. Other medical therapies and revascularization strategies were employed at the discretion of the treating physician. 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 US. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 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 US than elsewhere in the world. Baseline patient demographic and management features differed between the US and other countries. The median hospital length of stay was shorter in the US (5 days, interquartile range, 3–8 days) than outside of the US (10 days, 7–15 days). Patients enrolled in the US were more likely to have had the study drug administered for Direct thrombin inhibitors. Although the combination of anticoagulants (LMWH or unfractionated heparin) plus a GP IIb/IIIa inhibitor, such as eptifibatide, currently remains the evidence-based standard for managing high-risk patients with NSTE-ACS undergoing PCI, direct thrombin inhibitors have also been evaluated in lower-risk patients undergoing PCI.55 REPLACE-2 randomized 6,010 PCI patients (77% in the US) to heparin plus a IIb/IIIa blocker (eptifibatide or abciximab) or to bivalirudin alone with the provisional addition of a IIb/IIIa blocker if needed in a double-blind, triple-dummy design. The objective of the trial was to establish whether it would be possible to use IIb/IIIa blockers selectively rather than routinely in low-risk patients if heparin were replaced by bivalirudin.55 Planned IIb/IIIa blocker treatment was actually given to 0.07% of the bivalirudin group and 96.3% of the heparin plus IIb/IIIa blocker group and provisional IIb/IIIa blocker treatment was given to 7.2% of the bivalirudin group and 5.2% of the heparin plus IIb/IIIa blocker group. The primary endpoint was a quadruple composite of death/MI/urgent revascularization at 30 days and major in-hospital bleeding. The secondary endpoint was the triple composite of death/MI/urgent revascularization. The primary quadruple endpoint showed a trend toward benefit with bivalirudin, but the secondary triple endpoint showed a preferential trend toward the heparin plus IIb/IIIa blocker group, both differences being nonsignificant. The REPLACE-2 results indicate that patients primarily undergoing low-risk PCI treated with bivalirudin and provisional use of GP IIb/IIIa inhibitors experienced a trend toward higher rates of myocardial infarction at 30 days versus those treated with unfractionated heparin and planned GP IIb/IIIa inhibitor therapy (7.0% versus 6.2%; p = 0.26), including a 41% increase in the occurrence of large MIs (CK-MB > 5x ULN) (2.4% versus 1.7%; p = non-significant). Published reports have shown that patients experiencing peri- and post-procedural MI are at increased risk of long-term mortality, especially in patients that suffered CK-MB elevations > 5x ULN after the performance of PCI. Based on the results of REPLACE-2, there is insufficient evidence to support routine use of bivalirudin in acute patients with moderate-to-high risk ACS undergoing PCI. 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. Data from ESPRIT and EPISTENT showing an estimated 30% reduction in 1-year mortality are consistent with recent meta-analyses demonstrating a significant ~40% overall survival benefit for patients receiving GP IIb/IIIa inhibitors administered as standard therapy during PCI. One group examined data from 5 trials that included > 5,000 patients with stent implantation. In this analysis, the standard use of GP IIb/IIIa inhibitors during PCI plus stenting prevented 11 deaths for every 1,000 patients treated.56 In contrast, direct thrombin inhibitors, including bivalirudin, have not been shown to reduce mortality in PCI for patients with moderate-to-high risk ACS. Data from the original BAT trial comparing bivalirudin and unfractionated heparin in PTCA showed a higher incidence of in-hospital death in patients treated with bivalirudin versus heparin (0.4% versus 0.2%, respectively; p = 0.27). Similarly, the rate of death at 6 months trended higher in the high-risk subgroup of patients with post-infarction angina (1.8% versus 1.1%; p = 0.09). Finally, bivalirudin has not demonstrated a significant reduction in the incidence of PCI-related MI compared with patients treated with heparin alone. Finally, it should be noted that REPLACE-2 was a non-inferiority trial comparing bivalirudin to a combination of heparin plus a GP IIb/IIIa inhibitor as the pharmacological standard for ACS patients undergoing PCI. However, more recent studies suggest that better outcomes in a high-risk population may be achieved using the combination of a LMWH (enoxaparin) plus the GP IIb/IIIa inhibitor eptifibatide, as compared to heparin plus a GP IIb/IIIa inhibitor.35 In INTERACT, as compared to patients receiving heparin, patients in the enoxaparin group were less likely to experience ischemia as detected by continuous ECG evaluation (primary efficacy outcome) during the initial (14.3% versus 25.4%; p Oral platelet antagonists. Based on analysis of multiple studies45,50–52 evaluating the benefits and risks of clopidogrel therapy in patients managed medically or with PCI, the CATH Consensus Panel issued recommendations for the use of this oral antiplatelet antagonist as part of the spectrum of care for patients with ACS. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial was designed to compare the efficacy and safety of early and prolonged use of clopidogrel plus aspirin with that of aspirin alone in patients with ACS.45 In the CURE trial, a total of 12,562 patients who presented within 24 hours after the onset of symptoms were randomly assigned to receive either clopidogrel (300 mg immediately, followed by 75 mg once daily) or placebo, in addition to aspirin (81–325 mg PO QD), for 3–12 months (mean, 9 months). The primary study endpoint (a composite of death from cardiovascular causes, nonfatal MI or stroke) occurred in 9.3% of the patients in the clopidogrel plus aspirin group and 11.4% of the patients in the aspirin only group (RR with clopidogrel as compared with placebo, 0.80; 95% CI, 0.72–0.90; p 3 µg/dl); 3) age older than 65 years; 4) presence of ST-T wave changes; 5) TIMI Risk Score >= 5; 6) diabetes; and/or 7) clinical instability in the setting of suspected NSTE-ACS. Additional factors that may suggest the need for more intensive medical therapy or that support early catheterization and revascularization as the dominant approach include the presence of such comorbid conditions as advanced renal disease, heart failure, or the presence of other co-existing risk factors, which, in the clinician’s judgment, suggest that maximally intensive pharmacotherapeutic approaches combined with interventional modalities will yield optimal patient outcomes.