非ST段抬高性心肌梗死PCI术后应用抗血小板药物的更新

C©2008, the Authors Journal compilation C©2008, Blackwell Publishing, Inc. DOI: 10.1111/j.1540-8183.2007.00335.x ACUTE CORONARY SYNDROME Current Update on Glycoprotein IIb-IIIa and Direct Thrombin Inhibition in Percutaneous Coronary Intervention for Non-ST Elevation Acute Coronary Syndromes: Balancing Bleeding Risk and Antiplatelet Efficacy ANDREW T. KWA, M.D., and JASON H. ROGERS, M.D. From the Division of Cardiovascular Medicine, University of California, Davis, Davis, California Appropriate pharmacologic treatment for patients with acute coronary syndromes (ACS) remains a matter of con- troversy. Additionally, a substantial gap exists between recommended guidelines and current clinical practice. Questions remain regarding which antiplatelet/antithrombotic treatment strategies are appropriate for individ- ual patients, based on their risk. We explore the role of glycoprotein IIb-IIIa inhibitors and the direct thrombin inhibitor bivalirudin in ACS patients, and consider the difficulties involved in reducing ischemic events while lim- iting bleeding risks. In patients with ACS who are undergoing percutaneous coronary intervention, high levels of microembolization and myocardial necrosis are potential risk factors for adverse long-term outcomes. Intensive an- tiplatelet/antithrombotic regimens may substantially affect these factors. Determination of risk levels, with the goal of targeting aggressive antithrombotic and interventional therapies to patients at higher risk, will help physicians choose appropriate pharmacologic therapy for patients with ACS. (J Interven Cardiol 2008;21:107–117) Introduction Given our current understanding of the processes that govern plaque rupture and thrombosis, antiplatelet and anticoagulant therapies are cornerstone therapies for patients with acute coronary syndromes (ACS). Un- til recently, among patients undergoing percutaneous coronary intervention (PCI), the standard of care has been oral aspirin with or without a thienopyridine (gen- erally clopidogrel) and unfractionated heparin, along with intravenous infusion of a glycoprotein IIb-IIIa in- hibitor if high-risk features are present. More recently, the direct thrombin inhibitor bivalirudin has come into common use among patients undergoing PCI, particu- larly those at lower risk for events. The large number of agents and treatment paradigms available to manage periprocedural risk for thrombotic Address for reprints: Jason H. Rogers, M.D., Cardiovascular Re- search Unit, Division of Cardiovascular Medicine, UC Davis Med- ical Center, 4860 Y Street, Suite 2820, Sacramento, CA 95817. Fax: 916-734-3764; e-mail: jason.rogers@ucdmc.ucdavis.edu events has understandably led to confusion and dis- pute regarding the best strategies for patients at differ- ent levels of risk. Moreover, appropriate management of patients with ACS requires coordination among a broad range of care providers, increasing the need for attention at all points along the complicated care path- way of these patients. Appropriate risk stratification is the first step toward selecting appropriate pharma- cologic therapy and improving outcomes. The under- lying principle of risk stratification is to target more aggressive antithrombotic and interventional therapies to patients at higher risk levels. The thrombolysis in myocardial infarction (TIMI) risk score, designed for use at the time of initial unstable angina or non-ST- segment elevation (NSTE) ACS patient assessment,1 is a means of integrating various clinical factors and markers into a single, comprehensive risk stratifica- tion tool (Fig. 1). Keeping these TIMI risk score levels in mind for every patient with unstable angina/NSTE ACS will help physicians stratify their degree of risk appropriately, which in turn guides pharmacologic therapy. Vol. 21, No. 2, 2008 Journal of Interventional Cardiology 107 KWA AND ROGERS Figure 1. Proposed treatment algorithm for unstable angina/NSTE ACS. Treatment selection can be based on TIMI risk score, identifying appropriate agents for use in patients at low-, intermediate-, and high-risk levels. ∗Consider holding if patient receiving glycoprotein IIb/IIIa and if multivessel disease/need for CABG suspected; ‡Family history of CAD, hypertension, hypercholesterolemia, diabetes, and current smoking; §Prior coronary stenosis of 50% or more. NSTE ACS = non-ST-segment elevation acute coronary syndrome; CAD = coronary artery disease; ACE = angiotensin-converting enzyme; TIMI = thrombolysis in myocardial infarction; CABG = coronary artery bypass grafting. Finally, balancing antiplatelet efficacy with bleed- ing risk should be the primary goal when choosing appropriate periprocedural pharmacologic therapy for patients who are undergoing interventions. This review will examine the evidence that supports the use of gly- coprotein IIb-IIIa inhibitors and/or bivalirudin in cur- rent treatment paradigms for patients at various risk levels. In addition, given that bivalirudin appears to be associated with a lower risk for bleeding, the balance among appropriate reductions in ischemic events while limiting the risks of bleeding will be explored. Glycoprotein IIb-IIIa Inhibitors in Patients with NSTE ACS An abundance of evidence points toward benefit as- sociated with glycoprotein IIb-IIIa inhibitors in 108 Journal of Interventional Cardiology Vol. 21, No. 2, 2008 GLYCOPROTEIN IIB-IIIA INHIBITORS AND BIVALIRUDIN IN NSTE ACS TREATMENT patients with NSTE ACS undergoing PCI, as well as in patients undergoing medical management alone.2–6 A meta-analysis conducted by Boersma and colleagues supports the benefits of glycoprotein IIb-IIIa inhibitors in patients with NSTE ACS. This study included 31,402 patients with NSTE ACS enrolled in six clini- cal trials that compared glycoprotein IIb-IIIa inhibitors with placebo or a control therapy.7 At 5 days after randomization, glycoprotein IIb-IIIa inhibitors were associated with a highly significant 16% relative re- duction in the risk of death or myocardial infarc- tion (MI) (P = 0.0003, driven primarily by reduc- tion in nonfatal MI), which was maintained through the 30-day follow-up. At 30 days after intervention, patients who received glycoprotein IIb-IIIa inhibitors had a 9% reduced risk of death or MI, compared with those who received placebo or control treat- ments (P = 0.015). Notably, these benefits were con- sistent across subgroups, including those stratified by traditional risk identifiers, such as age, history of diabetes or cardiac disease, and condition on ad- mission. These data, when taken together, have re- sulted in guidelines that recommend early, aggres- sive antiplatelet therapy, particularly among high-risk patients. The value of risk stratification using biomarkers is illustrated by the Intracoronary Stenting and An- tithrombotic Regimen-Rapid Early Action for Coro- nary Treatment (ISAR-REACT) trials. In the initial ISAR-REACT trial, the efficacy of the glycoprotein IIb-IIIa inhibitor, abciximab, was tested in 2,159 pa- tients at low-to-intermediate risk undergoing elec- tive PCI after pretreatment with clopidogrel.8 Patients were randomly assigned to treatment with abciximab or placebo, with background therapy of clopidogrel 600 mg, aspirin 325–500 mg, and heparin (either 70 U/kg for abciximab patients or 140 U/kg for placebo patients). The primary end-point was a composite of death, MI, and urgent target vessel revascularization at 30 days. The incidence of the composite primary end- point of death, MI, and urgent target vessel revascu- larization was 4% among patients who received abcix- imab and in those who received placebo.8 There was no difference in MI (4% in both groups). Patients in the abciximab group had marginally, though not sig- nificantly, higher risk for major bleeding than those in the control group (12/1,079 vs. 8/1,080, respectively; P = 0.37) and a significantly higher rate of pro- found thrombocytopenia (27/1,079 vs. 21/1,079, re- spectively; P = 0.002), although this adverse event was relatively rare. In contrast to ISAR-REACT, which enrolled primar- ily patients at low risk for events (i.e., those undergoing elective procedures), the ISAR-REACT 2 trial enrolled 2,022 patients with NSTE ACS undergoing PCI in pa- tients at higher risk for events, as indicated by elevated troponin levels at admission (defined as an increase of >3 times the upper limit of normal or an increase of ≥50% of the previous value if the pre-PCI level was higher than the upper limit of normal).9 The clinical end-points and pharmacologic treatments were consis- tent with ISAR-REACT. In ISAR-REACT 2, patients receiving abciximab demonstrated an overall 25% reduction in risk for the composite of death, MI, and urgent target vessel revas- cularization compared with placebo (P = 0.03).9 Im- portantly, this benefit was confined to 50% of patients who were at higher risk (as measured using troponin levels), whereas no difference in ischemic events was observed between the abciximab and placebo groups in patients without an elevated troponin level; the in- cidence of ischemic events was 29% lower in the ab- ciximab group than that in the placebo group among patients with elevated troponin levels (P = 0.02). The anti-ischemic benefit associated with abciximab was not associated with an increased rate of major or minor bleeding. In summary, the ISAR-REACT trials suggest that glycoprotein IIb-IIIa inhibitors add substantial value in patients at high risk for events, as assessed by ele- vations in troponin levels at admission, but these trials do not demonstrate clinically significant reductions in major adverse cardiac outcomes among patients at low- to-moderate risk. However, the importance of accurate risk assessment becomes apparent as we analyze these trials, since, by extension from the patient population enrolled in ISAR-REACT 2, possibly as many as half of all patients who undergo urgent PCI should be con- sidered at high risk, based on elevations of troponin level. Another important observation is that all pa- tients in the ISAR-REACT 2 trial received clopidogrel, 600 mg orally, at least 2 hours before the procedure. In clinical practice, clopidogrel may be withheld in pa- tients whose coronary anatomy is unknown or in whom multivessel disease is expected, based on an increased risk for serious bleeding among patients who receive clopidogrel within 5 to 7 days of coronary artery bypass grafting (CABG).10,11 Vol. 21, No. 2, 2008 Journal of Interventional Cardiology 109 KWA AND ROGERS The American College of Cardiology/American Heart Association (ACC/AHA) guidelines clearly en- dorse the use of clopidogrel for the acute management of patients with NSTE ACS, but also recommend with- holding clopidogrel for at least 5 days prior to surgery due to increased bleeding risk.12 Unfortunately, it re- mains difficult to reliably predict, prior to angiogra- phy, which patients will need eventual surgical revas- cularization, and the majority of NSTE ACS patients treated with clopidogrel in clinical practice undergo CABG in ≤5 days from treatment for a variety of po- tential clinical and economic reasons.13,14 Although as yet untested, this guideline-practice gap may provide an argument for sole upstream aspirin and glycoprotein IIb-IIIa platelet inhibition in patients felt to have mul- tivessel disease, although the inability to predict the coronary anatomy of these patients prior to angiogra- phy will make this approach difficult. Unfortunately, a significant gap exists in manage- ment of patients with unstable angina and NSTE ACS between clinical practice and recommended guidelines from the AHA/ACC. For instance, the latest revision of the guidelines12 confers a class IA recommenda- tion to upstream use of clopidogrel or glycoprotein IIb-IIIa inhibition in patients undergoing an initial in- vasive strategy. However, data from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA guidelines (CRUSADE) Quality Improve- ment Initiative analyzing selection patterns for early use (≤24 hours) of glycoprotein IIb-IIIa inhibitors in patients with high-risk NSTE ACS (i.e., ischemic chest pain of less than 24-hour duration and either positive cardiac markers or ischemic changes on electrocardio- gram) found that among 56,804 patients enrolled, gly- coprotein IIb-IIIa inhibitors were initiated during the first 24 hours in only 20,092 (35.5%).15 Patients at lower risk were more likely to receive this early treat- ment compared with patients who were at higher risk. Early use of glycoprotein IIb-IIIa inhibitors was asso- ciated with improved unadjusted in-hospital outcomes compared with no early glycoprotein IIb-IIIa inhibitor therapy. In particular, early use was associated with a reduced risk of death, the composite of death, MI, and congestive heart failure, as well as a shortened length of hospital stay. However, in this observational study, it is possible that the mortality benefit noted with gly- coprotein IIb-IIIa inhibitors may be related to the fact that those patients who received glycoprotein IIb-IIIa inhibitors may also have received more appropriate evidence-based therapies. Although confounding fac- tors cannot be ruled out in an observational study, these data suggest that substantial benefit may be derived by closing the gap between recommended guidelines and real-world clinical practice. Hospital participation in health quality improvement measures, such as CRU- SADE, is important, and has been shown to increase adherence to class I guidelines for NSTE ACS.16 Do Glycoprotein IIb-IIIa Inhibitors Add Value in Low- to Moderate-Risk Patients? Because fol- low-up in the ISAR-REACT series of studies did not extend beyond 30 days, conclusions cannot be drawn from these studies regarding the long-term im- pact of periprocedural glycoprotein IIb-IIIa inhibi- tion among patients who receive high-dose clopido- grel. The results of the ISAR-REACT trials do not clarify the risks associated with periprocedural mi- croembolism and subclinical events. Because platelets aggregate and disaggregate during thrombus forma- tion, microemboli may be released, resulting in mi- crovascular obstruction.17 PCI results in further me- chanical disruption of an unstable plaque, and it has been demonstrated that nearly all patients undergoing stenting have evidence of microembolization.18,19 Higher levels of microembolization and myocardial necrosis, as measured by release of cardiac enzymes, appear to have a long-term impact on outcomes (Fig. 2). An early study by Abdelmeguid et al.20 found that compared with patients without creatine kinase (CK)-MB elevation, patients with elevated CK-MB levels were at substantially higher risk for cardiac death (risk ratio [RR] 1.27; P = 0.04), MI (RR 1.31; P = 0.03), and major ischemic complications (RR 1.15; P = 0.01) after a mean of 36 months of follow- up. More recently, a study conducted by Brener and colleagues found that some myonecrosis occurred in 24% of patients undergoing planned coronary stent- ing,21 and that elevated CK-MB was independently as- sociated with death (odds ratio [OR] 1.89), death or MI (OR 1.78), and death, MI, and revascularization (OR 1.38).21 Among patients in the highest CK-MB quintile (≥10 times the upper limit of normal), the unadjusted mortality rate was 29.3% compared with 7.5–10.8% among patients in the lower CK-MB quin- tiles. This study, conducted in patients undergoing in- tervention according to contemporary practices, sug- gests not only that some degree of myocardial necrosis is common, but that at very high levels, it may also be a major risk factor for adverse outcomes over the long term. 110 Journal of Interventional Cardiology Vol. 21, No. 2, 2008 GLYCOPROTEIN IIB-IIIA INHIBITORS AND BIVALIRUDIN IN NSTE ACS TREATMENT Figure 2. Increased risk of adverse events with CK-MB release from PCI. CK-MB = creatine kinase-MB; PCI = percutaneous coronary intervention. It has been shown that glycoprotein IIb-IIIa inhibi- tion provides significant antiplatelet activity in addi- tion to standard therapy with aspirin and clopidogrel. A study conducted by Gurbel and colleagues, Clopido- grel Loading With Eptifibatide to Arrest the Reactiv- ity of Platelets (CLEAR PLATELETS), demonstrated that significant reductions in markers of myocardial necrosis can be achieved with glycoprotein IIb-IIIa in- hibitors even among low-risk patients undergoing elec- tive stenting.22 In this study, 120 patients undergoing elective stenting were randomized to clopidogrel at doses of 300 mg or 600 mg, with or without eptifi- batide. Compared with clopidogrel 600 mg alone, ad- dition of eptifibatide resulted in a ≥2-fold increase in platelet inhibition. Release of CK-MB was lowest in the groups that received eptifibatide (P < 0.005); tro- ponin and myoglobin release were also significantly lower among patients who received eptifibatide plus clopidogrel compared with those who received clopi- dogrel alone (P = 0.004 and P = 0.002, respectively). Similarly, the results of the Platelet Activity Extinc- tion in Non-Q Wave Myocardial Infarction With As- pirin, Clopidogrel, and Eptifibatide (PEACE) study in- dicate that eptifibatide provides significant additional antiplatelet activity over that provided by aspirin and clopodigrel.23 Conversely, the Intracoronary Stenting and Antithrombotic Regimen—Is Abciximab a Supe- rior Way to Eliminate Elevated Thrombotic Risk in Diabetics (ISAR-SWEET) trial enrolled 701 diabetic patients with coronary artery disease who underwent elective PCI after preloading with clopidogrel 600 mg at least 2 hours before the procedure. Patients were ran- domly assigned to receive abciximab or placebo at the time of PCI. At 1 year, there was no difference in the composite primary end-point of death and MI (8.3% ab- ciximab vs. 8.6% placebo; P = 0.91).24 Together, these data suggest that intensive antiplatelet/antithrombotic regimens may have a substantial impact on periproce- dural myonecrosis and on long-term outcomes among patients undergoing PCI. Bivalirudin in Current Treatment Paradigms As a result of recent trials and attendant guide- lines modifications, the use of glycoprotein IIb-IIIa in- hibitors has been partially supplanted by the use of bivalirudin, a direct thrombin inhibitor. This change in clinical practice is supported by two major trials: Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) and Acute Catheterization and Urgent Intervention Triage Strat- egy (ACUITY).25,26 In the randomized REPLACE-2 trial, patients un- dergoing urgent or elective PCI received bivalirudin (0.75 mg/kg bolus plus 1.75 mg/kg per hour during PCI) with provisional glycoprotein IIb-IIIa inhibition or heparin (65 U/kg bolus) with planned glycoprotein IIb-IIIa inhibition; glycoprotein IIb-IIIa inhibitors used in the trial included eptifibatide (at a dosage of two 180 µg/kg boluses 10 minutes apart followed by a 2.0 µg/kg infusion for 18 hours) or abciximab (at a dosage of 0.25 mg/kg bolus followed by 0.125 µg/kg infusion for 12 hours).27 Administration of clopidogrel, at a dosage of 300 mg 2–12 hours before intervention, was strongly recommended but not required. The pri- mary end-point was a quadruple composite of death, MI, severe MI requiring urgent or repeat procedures, or in-hospital major bleeding within 30 days of ran- domization. A secondary end-point that included all Vol. 21, No. 2, 2008 Journal of Interventional Cardiology 111 KWA AND ROGERS the components of the primary end-point except bleed- ing was also assessed. Notably, major bleeding was identified using novel criteria, including intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss resulting in a decrease in hemoglobin of >3 g/dL; any decrease in hemoglobin of