Platelet Glycoprotein IIb/IIIa Inhibitors: Overview and Implications for the Anesthesiologist

Spontaneous rupture of an atherosclerotic plaque in a coronary artery can lead to the spectrum of acute coronary syndromes (ACS) that includes unstable angina and acute myocardial infarction (MI). Plaque disruption during percutaneous coronary interventions (PCI) is an inevitable part of the procedure for enlargement of the arterial lumen and can also lead to coronary artery occlusion. The importance of platelets in the pathophysiology of acute coronary thrombosis is now well recognized (1). Over the past decade, research has focused on controlling the platelet response to vascular injury. Several new potent inhibitors of platelet aggregation have been developed as a means of reducing the ischemic complications of ACS and PCI. This review will summarize the current concepts and issues surrounding the use of glycoprotein (GP) IIb/IIIa inhibitors in the management of patients with coronary artery disease. Pathophysiology of Plaque Rupture GP IIb/IIIa receptors are membrane GPs that are present on the cell surface. Each platelet contains approximately 80,000–100,000 GP IIb/IIIa receptors. Rupture of a coronary plaque is followed by adhesion of platelets to the newly exposed subendothelium. This leads to platelet activation, resulting in platelet degranulation, which releases chemotactic factors, clotting factors, and vasoconstrictors (2). Once activated, platelet GPs undergo a conformational change that permits the binding of their principal ligand, fibrinogen (Fig. 1). Cross-linking through fibrinogen allows platelets to aggregate into a growing hemostatic plug. Regardless of what triggers the platelet to activate, GP IIb/IIIa receptors represent the final common pathway to platelet aggregation and thrombus formation (2). Therefore, inhibition of platelet GP IIb/IIIa receptors is a logical strategy for controlling the platelet response to vascular injury.Figure 1: Platelet activation and aggregation. Reprinted with permission from Madan et al. (1). GP = glycoprotein.Platelet Inhibitor Pharmacology Three GP IIb/IIIa inhibitors are currently available for clinical use in North America. These are abciximab (ReoPro™), eptifibatide (Integrilin™), and tirofiban (Aggrastat™). Abciximab is a large monoclonal antibody, whereas eptifibatide and tirofiban are synthetic small-molecule GP IIb/IIIa inhibitors. There are important differences in the pharmacological properties of these drugs (Table 1). Typical dosing protocols are summarized in Appendix 1.Table 1: Characteristics of Glycoprotein IIb/IIIa InhibitorsAbciximab is the most extensively studied drug. It is a large molecule composed of the variable portion of mouse-derived Fab fragment linked to the constant region of the human immunoglobulin G Fab moiety (1). Abciximab binding is nonspecific; in addition to the GP IIb/IIIa receptor, this drug is capable of binding to the vitronectin receptor on vascular smooth muscle cells as well as the MAC-1 receptor on monocytes. Inhibition of vitronectin receptors and MAC-1 receptors may contribute to the antiinflammatory properties of abciximab, although the clinical significance of these interactions has not been determined (3,4). Because of the high-affinity binding of abciximab to the GP IIb/IIIa receptor, the low dissociation constant (Kd) is thought to account for the prolonged antiplatelet effect of the drug after cessation of a continuous infusion. Flow cytometry studies have detected abciximab on circulating platelets up to 2 wk after discontinuation of treatment. After an initial dose, the drug is avidly receptor bound (67%), with little free abciximab circulating in the plasma (5). This property has an important clinical implication in situations in which rapid abciximab reversal is desired. Platelet transfusion will be effective in increasing the pool of circulating platelets and their available GP IIb/IIIa receptors. Abciximab molecules will redistribute over the entire receptor pool, thereby diluting the drug’s antiplatelet effect (4–7). In contrast, the small-molecule inhibitors eptifibatide and tirofiban inhibit the GP IIb/IIIa receptor with low affinity but high specificity properties. These drugs bind to the GP IIb/IIIa receptors in a competitive and rapidly reversible manner. At steady-state, there is a large quantity of drug molecules circulating in the plasma. Platelet transfusions may not be effective in reversing the antiplatelet effect of eptifibatide or tirofiban because large quantities of unbound drug are rapidly redistributed to the new platelet receptors. Both eptifibatide and tirofiban exhibit first-order kinetics and have a short duration of antiplatelet effect compared with abciximab (Table 1). The pharmacokinetic modeling of abciximab in humans is not well understood. The elimination half-lives of eptifibatide and tirofiban range from 2 to 3 h, whereas that of abciximab is 30 min (3). Further details can be seen in Table 1. Clinical Studies Several multicenter clinical trials have evaluated the efficacy of GP IIb/IIIa inhibitors for PCI and, more recently, for ACS (Table 2) (8–10,11–20). These trials have been extensively reviewed elsewhere (1,21). Thus, only a brief overview is presented.Table 2: Landmark Clinical Trials for PCI and ACSThe first large-scale randomized trial compared abciximab with placebo in approximately 2100 patients undergoing elective PCI (11). Abciximab therapy resulted in a 35% relative risk reduction (RRR) in the composite end-point of death, MI, or urgent repeat revascularization (either PCI or emergency coronary artery bypass graft [CABG]). In the elective PCI population, more studies followed. The RRR achieved by GP IIb/IIIa inhibitors compared with placebo ranged from 22% to 56%. Not only was there benefit in the short term (30 days), but a recent pooled analysis of 5799 PCI patients comparing abciximab with placebo showed a long-term reduction in 3-yr mortality rate by 22% (6.3% versus 5%;P = 0.03) among abciximab-treated patients (22). Although benefits have been demonstrated with all three drugs in the PCI population, the most experience has accrued with abciximab. The increased cost of abciximab compared with eptifibatide and tirofiban has limited its widespread use during PCI (Table 1). Nevertheless, abciximab was shown to benefit high-risk patients, including those with acute MI, reduced left ventricular function, diabetes, multivessel disease, and complex coronary anatomy (23). As a result, abciximab is often reserved for these high-risk patients undergoing PCI. In the setting of ACS, GP IIb/IIIa inhibitors were evaluated in five randomized controlled trials (Table 2) (8,9,12–14). The primary end-point for these trials was the combined incidence of death or MI measured at 30 days. Relative to the PCI trials, the magnitude of benefit imparted by GP IIb/IIIa inhibitor therapy was less robust (overall RRR for death or MI ranged from 12% to 15%). The combination of tirofiban with heparin (13), or of eptifibatide with heparin (9), was demonstrated to be superior to heparin alone for the treatment of ACS (Table 2). However, the practice of administering a GP IIb/IIIa inhibitor alone, without any concomitant heparin therapy, was demonstrated to be potentially detrimental (12). Abciximab therapy, either as a 24- or 48-h infusion, was evaluated in combination with heparin for the management of ACS compared with heparin therapy alone (8). All patients received concomitant aspirin therapy. Paradoxically, the prolonged infusion of abciximab therapy was associated with an increased rate of death or MI. Consequently, high-risk patients presenting with ACS are predominantly treated with small-molecule GP IIb/IIIa blockade. The strategy of combining small-molecule GP IIb/IIIa inhibitors plus heparin with an early invasive strategy (including early angiography or revascularization) was particularly beneficial in reducing the 30-day incidence of death or MI (24). The incidence of major bleeding in the ACS trials was small overall, but it was slightly increased in patients treated with platelet inhibitors (range, 0.4%-01.3%) compared with placebo controls (range, 0.4%–3%) (8,9,12–14). The overall incidence of intracranial hemorrhage was small and similar in the two treatment groups in each respective trial (0%–0.3%) (25). In summary, convincing evidence supports the use of platelet GP IIb/IIIa inhibitors for patients undergoing PCI. Consequently, most patients undergoing PCI in North America will likely receive a GP IIb/IIIa inhibitor along with aspirin and heparin, unless there are contraindications. Of those patients undergoing PCI, 80%–90% will undergo coronary stent implantation. This subset of patients will receive adjunctive antiplatelet therapy, including aspirin and either ticlopidine or clopidogrel, to prevent subacute stent thrombosis (26). Both ticlopidine and clopidogrel inhibit platelet aggregation by direct inhibition of the adenosine diphosphate receptor. Discussion of these antiplatelet drugs is beyond the scope of this review. For ACS, evidence supporting the efficacy of GP IIb/IIIa inhibition is less robust. Nevertheless, eptifibatide and tirofiban are still considered beneficial, particularly for selected high-risk patients, such as those with positive cardiac enzyme markers or dynamic electrocardiographic changes (ST depression, T-wave inversion, or transient ST elevation). Complications Bleeding Bleeding complications represent a significant limitation to the effectiveness of GP IIb/IIIa inhibitors. Most studies that examined the incidence and extent of bleeding classified the severity according to the Thrombolysis in Myocardial Infarction (TIMI) trial (27). Major bleeding was defined as intracranial hemorrhage or observed bleeding associated with a decrease in hematocrit of ≥15% or a decrease in hemoglobin of ≥50 g/L. Minor bleeding was defined as spontaneous gross hematuria or hematemesis or observed bleeding associated with a decrease in hematocrit of ≥10% or a decrease in hemoglobin of ≥30 g/L but <50 g/L (25,27). PCI Bleeding. An increased rate of bleeding with GP IIb/IIIa inhibitors was first noted in the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial, which evaluated abciximab in patients undergoing PCI (11). Major bleeding was observed in 14% of abciximab-treated patients compared with 7% of placebo-treated controls (P = 0.001). Most bleeding occurred at the vascular access site (28). Independent predictors of bleeding, by multivariate regression analysis, included older age, low body weight, female sex, evolving MI, therapy with abciximab, and the duration and complexity of the interventional procedure (29). During PCI, the risk of bleeding, particularly from the vascular access site, in patients receiving GP IIb/IIIa inhibitors was reduced by using small-dose weight-adjusted heparin (70 U/kg), by avoidance of postprocedural heparin, and by early vascular sheath removal (4–6 h postprocedure) (30). These modifications of periprocedural care have resulted in comparable bleeding rates for both treated and control patients in contemporary clinical trials (17,20). CABG-Related Bleeding. The early experiences with emergency CABG after failed PCI demonstrated increased mortality rates, significant bleeding, and large transfusion requirements in patients treated with GP IIb/IIIa inhibitors (31). In the EPIC study, 58 of 2099 patients required emergency CABG (32). Among these patients, the mortality rate for abciximab-treated patients was more frequent than for placebo-treated patients (29.4% versus 8%) and significantly more frequent than for historical controls (approximately 6% for emergency CABG) (33). Major bleeding related to bypass surgery (>50 g/L decrease in hemoglobin) occurred in 100% of abciximab-treated patients and 72% of placebo-treated patients (P = not significant). Data from the EPIC (11), EPILOG (17), and Evaluation of Platelet IIb/IIIa Inhibitor for Stenting (EPISTENT) (20) studies indicated that 50%–66% of the major bleeding episodes were related to surgery. The PURSUIT (9) study compared eptifibatide with placebo for the management of ACS and showed that patients undergoing CABG (in both the control and treated groups) accounted for 80% of the major bleeding events. Gammie et al. (34) reported their experience with 11 patients that required emergency CABG after failed PCI and abciximab therapy (34). Six of the 11 patients underwent early surgery, <12 h (range, 1–3 h) after the administration of abciximab. Most patients were given 300 U/kg of heparin for cardiopulmonary bypass (CPB). These six patients had a significantly longer maximum activated clotting time (ACT) during the surgery (median, 800 versus 528 s), significantly larger blood loss, and larger requirements for the transfusion of blood products (median, 30 versus 0 U;P < 0.05) compared with patients who underwent surgery later than 12 h after abciximab administration. This led to the suggestion that bleeding risk in cardiac surgery patients was increased within 12 h of abciximab therapy and would decrease thereafter. Realization of the independent anticoagulant effect of GP IIb/IIIa inhibitors (particularly abciximab and eptifibatide) and the increased bleeding risk associated with large-dose heparin in combination with abciximab led to subsequent clinical trials evaluating the GP IIb/IIIa inhibitors in PCI populations with reduced heparin dosing (15). The significant reduction in bleeding complications comparable to that of placebo rates was a direct result of altered periprocedural practices. Weight-adjusted heparin dosing, concomitant ACT monitoring, and early femoral sheath removal are now the current standards of practice during PCI. This experience has led to the suggestion that a reduction in heparin dosing during CPB would also decrease the bleeding risk in an emergency CABG situation. Excessive bleeding was particularly a concern if surgery could not be delayed until after platelet function had returned to normal (25,34). In the cardiology literature, suggestions for management of patients have been presented when PCI has failed and emergency CABG is then required. A reduced heparin dosing protocol in this particular situation has also been suggested (3,25). These suggestions, however, have not been formally evaluated. Some of these suggestions are presented in Table 3(25).Table 3: Management Suggestions After Failed PCIThe extrapolation of reduced heparin dosing from the PCI literature to the setting of emergency cardiac surgery has been the subject of controversy (35). One major concern associated with reducing the standard dose of heparin (300 U/kg) is the potential for underdosing, given the variability in ACT measurements (36). Factors such as hypothermia, CPB-related platelet dysfunction, concomitant drug therapy (such as aprotinin), and hemodilution alter (prolong) ACT measurements during cardiac surgery (37). Moreover, although platelet transfusion is considered the mainstay treatment for management of perioperative bleeding with abciximab therapy, there is no consensus as to the timing or dosing of platelets in cardiac surgery. Traditionally, once a surgical cause and incomplete heparin reversal are excluded, only then is a platelet transfusion considered (38). Furthermore, Steinhubl et al. (39) demonstrated considerable interpatient variability in recovery from platelet inhibition after therapy with GP IIb/IIIa inhibitors, a finding that may have important implications for reversal of GP IIb/IIIa blockade. Although somewhat controversial, the use of prophylactic platelet transfusions has been advocated by some centers (36,40). Juergens et al. (40) reported prophylactic platelet administration in three patients during weaning from CPB and in one patient before arrival in the operating room. These patients underwent surgery within 6 h after receiving abciximab therapy after failed PCI (40). All four patients underwent full heparinization for CPB, along with prophylactic platelet transfusions (the total number of units was not specified). One patient experienced major blood loss (decrease in hemoglobin >50 g/L), but all patients survived the surgery and were discharged (40). On the basis of these results, the authors suggested that prophylactic platelet transfusion in such patients “appeared reasonable.” Lemmer et al. (36) described 12 patients who underwent emergency CPB surgery within 12 h of abciximab therapy (range, 0.5–10 h). All patients received heparin at a dose of 450 U/kg body weight (plus 10,000 U in the pump-prime solution) and a prophylactic platelet transfusion after protamine administration. Patients were transfused an average of 3.6 U of red blood cells, and no patient had a significant platelet-related coagulopathy (36). With better understanding of the pharmacology of these drugs and the advent of short-acting GP IIb/IIIa inhibitors, CABG surgery can be performed without significant bleeding. For example, one trial compared eptifibatide to placebo in 10,049 patients undergoing ACS (9). Seventy-eight of these patients required CABG, including 32 patients who underwent CABG within 2 h of discontinuing eptifibatide therapy (41). The incidence of major bleeding, as defined by the Thrombolysis in Myocardial Infarction criteria (27), was similar in both the eptifibatide and placebo groups (64% versus 63%;P = not significant). The incidence of blood transfusions was similar in both treatment arms (59.4% and 56.5% for the eptifibatide and placebo groups, respectively) (41). Furthermore, the 30-day mortality rate was similar (eptifibatide 6.3% versus placebo 6.5%;P = 0.962). Notably, postoperative platelet counts were significantly higher in the eptifibatide group. Fortunately, the widespread use of coronary stenting during PCI in conjunction with GP IIb/IIIa inhibition has resulted in an overall decreased need for emergency CABG because of failed PCI. In the EPISTENT trial, rates of emergency CABG ranged from 0.6% to 1.1% among the three treatment groups (20). In the Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II trial (19), emergency CABG within 24 h of randomization was required less frequently in eptifibatide-treated patients (1.1% and 1.2% versus 2.1% among placebo-treated controls) (33). Thrombocytopenia Thrombocytopenia is an uncommon, rarely fatal, but nonetheless worrisome complication of GP IIb/IIIa inhibitors. The incidence of thrombocytopenia varied in the clinical trials but was observed more frequently with abciximab and tirofiban (range, 0.2%–1.6% for platelet counts ≤50 × 109/L) than with other drugs defined as a decrease in platelet to × within 24 h of receiving an initial dose, was observed in of patients treated with abciximab and of patients after the of abciximab thrombocytopenia was reported in of patients receiving eptifibatide therapy The GP IIb/IIIa thrombocytopenia is not well understood. Because heparin is often with GP IIb/IIIa inhibitors, thrombocytopenia be that thrombocytopenia and GP IIb/IIIa thrombocytopenia are presented in Table or a decrease in the platelet is also a Because of in the platelet and the platelet with or heparin a normal platelet (3). for the management of thrombocytopenia related to GP IIb/IIIa inhibition are in Thrombocytopenia to GP IIb/IIIa or 2: Management suggestions for = blood = = GP = from Madan et al. The administration of GP IIb/IIIa inhibitors during PCI or for the management of ACS is (Table 1). However, in the particularly in the setting of coronary have demonstrated these drugs to be are by a decrease in complications of ischemic The for abciximab compared with placebo in the EPISTENT trial was In the trial, the for eptifibatide compared with placebo was for The GP IIb/IIIa receptor inhibitors are rapidly the standard of care in coronary care particularly in there are PCI The use of these drugs in high-risk cardiac patients has implications for PCI and emergency surgery Furthermore, the use of these drugs for patients undergoing surgery could also the of that the time for emergency or elective surgery in patients treated with GP IIb/IIIa inhibitors have not been emergency surgery is GP IIb/IIIa inhibitors and heparin therapy be be given to the surgery for at h after discontinuation of abciximab and h after eptifibatide or tirofiban therapy. However, the of the surgical emergency may this clinical studies are available to for these Each be Management is left to the and understanding of the pharmacology of these In the setting of elective surgery, the antiplatelet effect of GP IIb/IIIa inhibitors no longer be For patients who have elective PCI with stent elective surgery be delayed at wk to of the antiplatelet and of the new Several of stent thrombosis with MI, and death have been reported after discontinuation of antiplatelet therapy and for elective surgery In one study of patients, those who underwent before elective surgery within of the surgery had the risk of cardiac compared with controls et al. evaluated patients who underwent coronary stent wk before surgery All all acute MI and of 11 major bleeding occurred in patients undergoing surgery within 2 wk after of the occurred in patients undergoing surgery 24 h after and all ischemic occurred in the of the The authors that surgery for wk after coronary stenting would the risk of stent thrombosis and bleeding Although GP IIb/IIIa inhibition was not and was not an in these these the need for with the interventional and to the and benefits of discontinuing antiplatelet therapy in such complex The time required after surgery for administering these drugs in of postoperative ACS or acute MI is also the and benefits of GP IIb/IIIa inhibitors be in with the and the potential use of these drugs for patients with acute vascular or could the care of this high-risk The platelet GP IIb/IIIa inhibitors have been to and long-term ischemic complications for patients undergoing PCI and for those presenting with These drugs are rapidly as part of the standard in the management of cardiac need to be with these drugs and their with the and potential complications of GP IIb/IIIa inhibitors will to the perioperative management of high-risk cardiac patients and may surgical to for review and and for

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