CEU OFFERING: Advances in Adjunctive Pharmacotherapy for Patients Undergoing PCI

Learning Objectives. At the conclusion of this activity, the participant should be able to: Explain how thrombi are generated and their role in acute coronary syndromes Describe the multiple pathways leading to platelet activation Define the role of different adjunctive therapies in inhibiting thrombus formation Compare the efficacy and safety of different adjunctive therapies in patients undergoing percutaneous coronary intervention (PCI) Activity instructions. Successful completion of this activity entails reading the article, answering the test questions and obtaining a score of over 70%, and submitting the test and completed evaluation form to the address listed on the form. Tests will be accepted until the expiration date listed below. A certificate of completion will be mailed to you within 60 days. Estimated time to complete this activity: 1 hour Initial release date: March 31, 2003 Expiration date: March 31, 2004. Target audience. This educational activity is designed for registered nurses. Accreditation statements. Nurses: Provider approved by the California Board of Registered Nursing, Provider Number 13255 for 1 contact hour. Radiologic Technologists: This activity is approved for 1 Category A CE credit by the ASRT. Expiration Date: 9/1/04. Commercial support disclosure. This educational activity has been supported by an educational grant from Eli Lilly Company. Faculty disclosure information. All faculty participating in Continuing Medical Education programs sponsored by HMP Communications are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation. Dr. Yoder has disclosed that he is a member of the speakers’ bureau for Eli Lilly and Company, The Medicines Company, Aventis, and Pharmacia. ___________________________________________________________ Percutaneous coronary intervention (PCI) plays an increasingly important role in the management of unstable coronary syndromes. An early invasive strategy has been shown to reduce the incidence of major cardiac events in unstable angina/non-ST- segment elevation myocardial infarction (UA/NSTEMI) patients, and is widely advocated as the preferred strategy in most patients with unstable coronary artery disease. First-line use of PCI for acute myocardial infarction (AMI) has also emerged as an effective reperfusion strategy that may improve survival and decrease morbidity. The last decade has seen great strides made in PCI in terms of both patient outcomes and its intrinsic safety. The development, refinement, and widespread implementation of stent technology has played an important role, but equally major advances have been made in adjunctive pharmacotherapy, leading to an explosion of potential new treatments for patients undergoing PCI. The PCI patient population represents a significant portion of the spectrum of diagnoses encompassed by the term acute coronary syndrome, which are: Unstable angina; Non-ST-segment elevation myocardial infarction; ST-segment elevation myocardial infarction (acute MI); Sudden cardiac death. Essentially, these diagnoses are all manifestations of an imbalance between myocardial oxygen supply and demand (i.e., myocardial ischemia). The most common cause of UA/NSTEMI is the development of a nonocclusive coronary thrombus on a disrupted atherosclerotic plaque, which narrows the lumen of the coronary artery and thus reduces myocardial perfusion.¹ Plaque rupture a potent trigger for thrombosis also causes approximately two-thirds of all AMIs. ² Thus, central to an understanding of the functioning and significance of different types of adjunctive therapy in PCI is an appreciation of the pathogenesis of thrombosis. Pathogenesis of Thrombus Formation The typical disease process leading to thrombus formation includes a chronic phase of atherosclerosis, which results in a modification of the blood vessel wall and development of an atherosclerotic plaque. As the lesion develops, a thin fibrous cap of extracellular-matrix proteins is formed over a lipid-rich core, comprised of cholesteryl esters and tissue factors. The acute phase of atherothrombosis is triggered by erosion, fission, or total rupture of the unstable plaque, which can result either from the action of shear forces on areas of the plaque vulnerable to mechanical stress (such as the plaque shoulder) or by the degradation of the fibrous cap by proteinases secreted by macrophages. This exposes the atheromatous core of the plaque, a potent substrate for thrombus formation. Exposure of the procoagulant tissue factor within the core initiates a complex cascade of platelet aggregation, thrombin generation, and fibrin deposition. Platelets play a central role in the development of arterial thrombosis. They adhere to the disrupted endothelium or ruptured plaque and become activated, fueling further platelet recruitment and aggregation, and stimulating thrombin generation. Indeed, platelets appear to play a dominant role in thrombin generation, accelerating its generation by some 5-6 orders of magnitude (reviewed in Walsh 1994, 3). Multiple activators at the site of vessel damage contribute to platelet activation, including ADP, thromboxane A2, thrombin, and collagen. Activated platelets undergo a critical conformational change of their membrane glycoprotein (GP) IIb/IIIa receptor proteins (integrins), converting them to a form that expresses high affinity for several ligands, including fibrinogen and von Willebrand factor. In this way, multiple platelets can associate through a complex network of fibrinogen cross-links to form a platelet-rich thrombus. Thrombin a key regulatory enzyme of the coagulation cascade promotes the conversion of fibrinogen to insoluble fibrin; this, in addition to the incorporation of circulating red blood cells caught by the mesh-like structure, further consolidates and stabilizes the platelet plug, leading to partial or total occlusion of the artery. Thrombosis is a key consideration in PCI patients. The presence of an intracoronary thrombus is an independent predictor of unsuccessful procedural outcomes. Patients with a confirmed or suspected thrombus are significantly more likely to experience angiographic failure, abrupt vessel closure, major dissection or total occlusion. ⁴ Thrombi are also implicated in periprocedural MI. However, intracoronary thrombi are not always readily visible by angiographic means. Thrombi are identified by angioscopy three times more often than by angiography, suggesting that thrombus is usually present in this patient population even when not readily visible by angiography. ⁵ This is an important consideration, since thrombi viewed angioscopically but not visible angiographically are strongly related to adverse outcomes after angioplasty. ⁵ Furthermore, it is not uncommon for arteries previously showing signs of only minimal stenosis to be subject to sudden full or partial occlusion by thrombus. Two-thirds of arteries in which a fully occlusive thrombus has formed as a result of plaque rupture show no more than 50% stenosis prior to the acute event, and the vast majority are less than 70% stenosed. ⁶ The significance of thrombus is particularly prominent in certain high-risk patient populations undergoing PCI who are at increased risk for ischemic complications and restenosis. These include patients with diabetes, patients with complex lesions, and patients with UA/evolving MI. For various reasons, each of these patient types presents unique challenges in the PCI setting. Patients with diabetes, who comprise 15-25% of cath lab patients, ⁷ generally have more extensive coronary artery disease and a higher incidence of unstable lesions than nondiabetics, and are at increased risk for postprocedural ischemic events. ⁸ This vulnerability may be associated with fundamental differences often seen in the platelet population in these patients (larger platelets, greater density of GP IIb/IIIa receptors on the platelet membrane, higher levels of platelet activity), as well as higher fibrinogen levels and smaller blood vessel morphology. These factors presumably also increase the risk of occlusive thrombus formation. Complex coronary anatomy, which is also associated with greater risk for ischemic complications and repeat revascularization, ⁹ has been shown to confer an increased risk of thrombus. Lesions with ACC/AHA type B (B1 and B2) and C morphologies are significantly more likely to exhibit intracoronary thrombus than the simpler type A lesions. ⁵ UA/NSTEMI patients who undergo a coronary intervention are at increased risk for ischemic complications compared with patients treated by revascularization for more stable indications, ¹⁰ and have a significantly higher incidence of angioscopic intracoronary thrombi than stable angina patients. ⁵ Tackling the thrombus quickly and effectively is particularly critical in patients with AMI, in order to restore blood flow to thrombus-obstructed vasculature and thus prevent mortality and minimize myocardial injury and loss. Adjunctive Pharmacotherapy in PCI A central consideration in adjunctive pharmacotherapy in PCI is the fine balance between the need to inhibit thrombus formation and the associated inhibition of mechanisms of normal hemostasis, potentially leading to serious bleeding complications such as hemorrhage. Thrombin formation and platelet activation both play significant pathophysiologic roles in the development of unstable coronary syndromes, and both antiplatelet agents and anticoagulants are effective against thrombosis. Antiplatelet agents are thought to work primarily by decreasing platelet aggregation, whereas anticoagulants are thought to work primarily by decreasing thrombin formation or inhibiting thrombin after it is formed. ¹¹ Antiplatelet Agents Aspirin The beneficial effects of aspirin in unstable angina were first established almost 20 years ago. ¹² Aspirin works by irreversibly blocking platelet cyclooxygenase, thus preventing formation of thromboxane A2 one of the stimulators of platelet aggregation and vasoconstriction. However, its effects on platelet aggregation and activation are primarily confined to this one pathway and it is unable to inhibit platelet adhesion. Thus, as an antiplatelet agent, aspirin is somewhat limited. However, it is both cheap and effective, and thus almost universally used as an adjunct to PCI. Gastrointestinal (GI) side effects limit its use in certain patient populations. ADP Inhibitors Ticlopidine and clopidogrel are thienopyridine-derivative oral antiplatelet agents that block ADP-mediated platelet aggregation and prevent the configuration transformation of the platelet fibrinogen receptor (GP IIb/IIIa) to its high-affinity form. Ticlopidine was the first to be marketed. Although associated with fewer GI side effects than aspirin, it has been associated with an increased incidence of reversible neutropenia and thrombocytopenia (13 Data from clinical trials support the benefits of clopidogrel in patients undergoing PCI. In the PCI substudy of CURE (see trial glossary for expanded trial names), which randomized UA/NSTEMI patients to either clopidogrel or placebo (in addition to aspirin), the strategy of clopidogrel pre-treatment followed by at least 28 days of clopidogrel therapy was shown to provide significant benefit in terms of reducing major cardiovascular events. ¹⁴ The recently announced results from the CREDO study of long-term clopidogrel therapy in PCI patients suggest this benefit persists when clopidogrel treatment is extended for at least 1 year. ¹⁵ Long-term clopidogrel treatment was not associated with a statistically significant increase in bleeding, although there was a trend towards an increase in major bleeding. GP IIb/IIIa Inhibitors The advent of GP IIb/IIIa inhibitors represented an important advance in the treatment of patients undergoing PCI. These agents inhibit the final common pathway of platelet aggregation by directly blocking the fibrinogen-binding receptor on the platelet surface and so offer a means to limit the adverse effects of plaque rupture, over and above that of other pharmacologic approaches. A 32,000-patient meta-analysis of the many placebo-controlled trials involving parenterally administered GP IIb/IIIa inhibitors has demonstrated how effective these agents are at reducing ischemic events, producing both an early and sustained benefit. ¹⁶ In contrast, oral agents have yielded disappointing results¹⁷ and none are currently approved for use. GP IIb/IIIa inhibitors have the potential to increase the risk of bleeding, particularly in the presence of anticoagulant agents such as heparin. Globally, PCI trials have shown that GP IIb/IIIa inhibitors are associated with approximate absolute increases of: 1% for major bleeding; 1% for thrombocytopenia (platelet count 18 Careful management of the access site and use of low-dose, weight-adjusted heparin can minimize the risk of bleeding complications. Although all three of the inhibitors currently on the market exhibit moderate-to-high affinity binding to the GP IIb/IIIa integrin, a class effect cannot be assumed, since there are important pharmacologic differences between the agents that contribute to their varying strengths and weaknesses as adjuncts to PCI. Abciximab, a large molecule monoclonal antibody fragment, was the first GP IIb/IIIa inhibitor to become commercially available in 1995. Abciximab has a short plasma half-life (30 minutes), but longer duration of action once bound to platelets. The slow dissociation of abciximab from platelets results in a gradual recovery of platelet function, which may contribute to its extended benefit in reduction of thrombotic complications after PCI. ¹⁹ In addition to high-affinity GP IIb/IIIa blockade, abciximab is able to cross-react with other integrins, and this aspect may contribute to its antithrombotic properties and overall clinical benefits. One such target is the vitronectin receptor (avb3), to which abciximab binds with equal affinity as to GP IIb/IIIa.20 It is believed that blockade of this receptor is associated with inhibition of thrombus formation by decreasing the number of platelets in thrombi and by interfering with the platelet activation events involved in facilitating thrombin generation. The inhibition of thrombin generation may contribute to both the immediate antithrombotic effects of abciximab and perhaps to its possible effects on long-term vascular restenosis. ¹¹ The inhibition of the leukocyte integrin Mac-1 (aMb2) by abciximab, along with its potential clinical effects, are less well understood. Mac-1 is expressed on monocytes and granulocytes and has various functions, including binding of factor X and accelerating its conversion to factor Xa (a catalyst for thrombin generation). By blocking Mac-1, it is believed that abciximab directly inhibits initiation of the coagulation cascade in addition to antiplatelet and antileukocyte effects. ²¹ Given the collective experience and established benefit in PCI, abciximab has become the reference standard for GP IIb/IIIa inhibition in the cath lab. ²² Clinical trials have demonstrated both the immediate and long-term efficacy and safety of this agent and shown that abciximab produces significant, consistent, and sustained reductions in ischemic complications in patients undergoing PCI, including MI and repeat revascularizations. ²³ Abciximab is also the only GP IIb/IIIa inhibitor to have demonstrated a significant long-term mortality benefit, based on extended follow-up of patients (median 4.8 years) enrolled to three randomized clinical trials. ²⁴ The availability of mortality data from a clinical study powered to detect mortality differences and in which detailed hospital billing records were collected has enabled the determination of the relative cost-effectiveness of abciximab as an adjunct to PCI. ²⁵ The cost-effectiveness analysis yielded a cost of about $6000 to $7000 per year of life saved, which compares favorably with other currently available therapies including dialysis at $30,000 to $60,000 per year of life saved, a de facto standard in the US. ²⁶ Abciximab has been shown to improve the safety profile for both balloon angioplasty and stenting in a variety of clinical settings. ^27-31 For patients with complex coronary anatomy undergoing stenting, the adjunctive use of abciximab has demonstrated an additive long-term benefit with respect to major ischemic events. ⁹ Furthermore, the relative benefit of abciximab in reducing ischemic events appears to be more pronounced among patients with complex lesions than in those with simple lesions. Abciximab therapy also appears to reduce the incidence of ischemic events in patients with diabetes undergoing PCI. Both prospective subgroup analyses of large, randomized clinical trials as well as retrospective observational analysis of a series of nonselected diabetic patients in a community setting have demonstrated a reduction in ischemic events in diabetic patients who were treated with abciximab. ^30,32 Eptifibatide and tirofiban are synthetic, small-molecule GP IIb/IIIa-inhibiting compounds a cyclic heptapeptide and a nonpeptide tyrosine derivative, respectively. Their inhibitory action is specific to GP IIb/IIIa and is competitive (i.e., they are not tightly bound to the GP IIb/IIIa integrin). Compared with abciximab, their platelet-bound half-lives are much shorter (2-2.5 h), ¹⁸ dictating the need for higher plasma levels and prolonged infusion to maintain efficacy. Reversal of the pharmacodynamic effect of these agents relies mainly on renal clearance of the drug. Despite their proven benefit in NSTEMI, the evidence for the use of eptifibatide and tirofiban as adjuncts to PCI has been less than definitive. ²² With the exception of ESPRIT, ³³ no single trial has demonstrated convincing benefit of small molecule inhibitors in PCI, although an overview of all trials points to consistent evidence of improved outcomes with these agents. ¹⁶ Even with the abundance of randomized, placebo-controlled clinical trials evaluating individual GP IIb/IIIa antagonists in PCI patients, important differences among agents, trial designs, and trial populations rendered it impossible to definitively determine from these a benefit of one agent over another. A head-to-head trial of tirofiban and abciximab was therefore undertaken to directly compare their safety and efficacy (TARGET). ³⁴ The trial was designed as a noninferiority trial for tirofiban, but unexpectedly, the primary endpoint a composite of death, MI and urgent target vessel revascularization at 30 days occurred more frequently in patients randomized to tirofiban than in those in the abciximab study arm. The rate of major bleeding was similar between the two study arms, although minor bleeding and thrombocytopenia occurred less frequently in the tirofiban arm. The TARGET study was not statistically powered to detect differences in intermediate- and long-term outcomes. At 6 months, the difference in composite event rate by treatment persisted, although the relative benefit of abciximab therapy had diminished because later events had accrued at a similar rate in the two arms. The absolute reduction in 30-day MI with abciximab was, however, maintained at 6 months. Anticoagulant Agents Unfractionated Heparin (UFH) The traditional anticoagulant adjunct in PCI, standard UFH has multiple sites of anticoagulant action. ³⁵ The anticoagulation effect of heparin is caused by a combination of inhibition of thrombin generation and inhibition of thrombin activity. Heparin binds to antithrombin and significantly enhances its inhibitory effects on coagulation factor Xa. The heparin molecule also has a binding site for thrombin itself, and has some inhibitory effects on a number of other coagulation factors. Although evidence-based support for UFH is relatively weak, the most recent ACC/AHA guidelines for the management of patients with UA/NSTEMI include a Class IA recommendation for parenteral anticoagulation with IV heparin.1 The benefits of UFH were accepted primarily on the basis of a single study, ³⁶ which demonstrated a significant reduction in MI and refractory angina with UFH compared with placebo. ³⁷ However, UFH has many undesirable features that may eventually render it obsolete, including its inconsistent anticoagulant effect. It inhibits only circulating thrombin, and thus has no effect on fibrin-bound thrombin; it is also unable to inhibit platelet-bound factor Xa. In addition, nonspecific cellular and protein binding of heparin dilutes its effect and leads to significant interpatient and intrapatient variability, necessitating frequent laboratory monitoring during use. Furthermore, UFH stimulates platelet activation, leading to a paradoxic prothrombotic state and reducing the beneficial effects of GP IIb/IIIa inhibitors. Postprocedural UFH has been linked to serious bleeding events and a rebound increase in ischemia has been reported on cessation of UFH treatment.38 Finally, an interaction between UFH and platelet factor 4, which is released by activated platelets, can lead to the formation of antibodies, resulting in type II heparin-induced thrombocytopenia (HIT) a potentially limb- and life-threatening immune-driven reaction that causes blood clots. Low-molecular-weight Heparins (LMWHs) Derived from chemical or enzymatic degradation of standard heparin, LMWHs offer a number of practical advantages over UFH, including a more predictable anticoagulant effect. The smaller size of these agents reduces nonspecific binding, yielding more predictable pharmacokinetics than standard heparin. Due to their mechanism of action, APTT monitoring is not required with these agents. LMWHs, which can be conveniently administered by subcutaneous injection, are less likely to be associated with thrombocytopenia than UFH, and so platelet count monitoring is also unnecessary unless treatment is extended for more than a few days. In terms of limitations, LMWHs share the same mode of action as UFH, and are therefore unable to inhibit fibrin-bound thrombin or platelet-bound factor Xa. In addition, they are contraindicated in patients with a history of HIT, due to a high rate of cross-reactivity with HIT antibodies. Two LMWHs are currently indicated for the prophylaxis of ischemic complications of UA/NSTEMI in the US enoxaparin and dalteparin. Recent meta-analyses of the LMWH class of agents compared with UFH suggest equivalent efficacy and safety in UA/NSTEMI patients, ^39,40 although two trials (TIMI 11B41 and ESSENCE42) have indicated that enoxaparin is more effective than UFH in reducing major ischemic events in patients with acute coronary syndromes (ACS), with benefits maintained out to one year. In the absence of head-to-head trials, however, it cannot be concluded on this basis that enoxaparin is superior to dalteparin, given the variability in study design and heterogeneity of enrolled patient populations in the noncomparative LMWH trials. Substantial evidence exists that patients receiving LMWH for an ACS can safely undergo cardiac catheterization and PCI. Indeed, retrospective analyses of comparative trials suggest that the superior therapeutic effect of enoxaparin relative to UFH is even more pronounced in patients who proceed to the cath lab than in those who are managed medically. In these trials, LMWH therapy was discontinued before catheterization, and interventional procedures were performed using UFH. However, more recent observational data suggest that once LMWH therapy has been initiated, it may be continued safely as a procedural anticoagulant, without switching to UFH. Although data from prospective, randomized clinical trials are lacking, increasing evidence supports the safety of concomitant administration of LMWH and GP IIb/IIIa inhibitors, ⁴³ with no increase in the risk of major hemorrhagic complications relative to that observed using UFH and GP IIb/IIIa. The observation that LMWHs do not activate platelets also raises the possibility that GP IIb/IIIa inhibition may be enhanced with concomitant LMWH. Direct Thrombin Inhibitors (DTIs) In contrast to heparin and LMWHs, DTIs are able to inhibit both fibrin-bound and circulating thrombin, and do not require endogenous cofactors in order to do so. They do not stimulate platelet activation and have no interaction with platelet factor ⁴, and so are not associated with HIT. Furthermore, they do not bind nonspecifically to plasma proteins, so the need for laboratory monitoring is reduced. However, since there is no known antidote for DTIs, bleeding complications must be managed by supportive care. ⁴⁴ A recent meta-analysis indicated that, as a group, the DTIs significantly reduce the risk of death or MI in patients with acute coronary syndromes compared with UFH. ⁴⁵ This benefit was maintained both at 30 days and 180 days, and appeared greatest in patients undergoing PCI. However, a lack of long-term benefit of DTIs over UFH is suggested by results of the HELVETICA trial, which failed to demonstrate an effect of treatment with hirudin on late restenosis following PCI. ⁴⁶ Hirudin, which was originally derived from the saliva of the medicinal leech, is a polypeptide DTI which binds irreversibly to both the fibrinogen-binding site and the active site of thrombin. By doing so, it blocks various effects of thrombin, including the conversion of fibrinogen to fibrin, activation of certain coagulation factors, and thrombin-mediated platelet activation. ^47,48 However, hirudin is only produced in trace amounts from leech extracts, and so a number of recombinant forms have been developed. Lepirudin is one such recombinant and is indicated as an alternative anticoagulant in patients with HIT. It has not been studied extensively in the setting of PCI, and appears to be associated with an increased risk of bleeding complications. ⁴⁹ Although its mode of action is similar to hirudin, the synthetic, bivalent DTI bivalirudin is a reversible inhibitor of thrombin, and thus has a shorter half-life. It also inhibits another potentially important player in the coagulation cascade, thrombin-induced plasminogen activator inhibitor-1.50 In clinical trials including the recent REPLACE-2 study bivalirudin has been shown to reduce the incidence of major ischemic events in patients undergoing angioplasty compared with conventional UFH. In addition, it has been associated with a significantly lower rate of bleeding complications. Although a number of univalent DTIs are currently under investigation, only one, argatroban, is currently approved for clinical use in patient undergoing PCI, and its use is limited to patients who have, or are at risk for, HIT (in whom UFH and LMWHs are contraindicated). Argatroban binds reversibly only to the active site of thrombin and is hepatically eliminated pharmacokinetic characteristics that make it attractive as an anticoagulant adjunct to PCI. However, a recent meta-analysis suggests univalent DTIs offer no benefit compared with heparin for the prevention of death or MI at the end of treatment and casts doubt on their potential efficacy for anticoagulation during PCI. ⁴⁵ Future Directions In the last ten years, the landscape of PCI has fundamentally changed, shaped in many ways by the availability of an increasing number of potent adjunctive antiplatelet and anticoagulant therapies. However, in spite of these advances, and even with the most recent antithrombotic regimen, overall morbidity and mortality rates in patients with acute coronary syndromes remain in the range of 10% or greater. ³⁵ Current research efforts may ultimately improve patient outcomes and lead to still greater clinical success in the future. A number of novel antithrombotic therapies are currently under investigation for use in patients undergoing PCI. These include new agents within existing therapeutic classes, such as the DTIs melagatran and ximelagatran, as well as inhibitors of upstream components in the coagulation cascade, such as tissue factor inhibitors and factor VII antagonists. In addition, the optimal pre-, peri- and postprocedural use of existing pharmacologic agents in specific patient populations must be defined, as well as the most beneficial therapeutic algorithm for transition to PCI. Large ongoing clinical trials, such as Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY), will likely generate important information in this respect. Finally, recent technologic breakthroughs in polymer science and stent design have led to the development of drug-eluting stents, which allow local delivery of immunosuppressive or antiproliferative agents directly at the site. These devices have shown great promise in their ability to inhibit the negative remodeling and intimal growth associated with stenting and may lead to a drastic reduction in the incidence of restenosis in PCI patients in the future. Summary Thrombi play a central role in acute coronary syndromes. Not only is thrombus formation on a disrupted atherosclerotic plaque the most common cause of acute coronary events, but an intracoronary thrombus is also a significant risk factor for unsuccessful procedural outcomes in patients undergoing PCI. In accordance with the significant pathophysiologic roles both platelet activation and thrombin formation have in thrombosis, the last decade has seen a proliferation in the number of antiplatelet agents and anticoagulants developed for adjunctive use in PCI patients. The newer antiplatelet agents include: ADP inhibitors, which block the ADP platelet receptor and thus prevent ADP-stimulated expression of the GP IIb/IIIa integrin, GP IIb/IIIa inhibitors, which block the final common pathway of platelet aggregation fibrinogen-mediated platelet crosslinking. Anticoagulants are believed to act by inhibition of thrombin formation or inhibition of thrombin after it is formed. UFH a long-time mainstay of anticoagulant therapy in revascularization procedures has a number of limiting features, and recent years have seen a shift towards LMWHs as a more practical alternative. More recently, DTIs have come to the forefront of anticoagulant research and may offer potential advantages over the indirect thrombin inhibitors, although a consensus has yet to be reached on the relative merits of each of these classes. FOR CEU QUESTIONS AND EVALUATION FORMS, PLEA

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