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Questions 1-3 list characteristics of platelet glycoprotein IIb/IIIa receptor antagonists. For each characteristic below, choose the single best answer: a. Competitive inhibitors (eptifibatide, tirofiban) Make your selection before scrolling beyond this point Answer: Drugs that inhibit a single mechanism of platelet activation have had limited success for preventing abrupt closure and/or restenosis. Potent inhibitors of the platelet glycoprotein (GP) IIb/IIIa receptor, the final common pathway of platelet aggregation, are much more effective inhibitors of platelet aggregation. Platelet IIb/IIIa receptor antagonists may be classified in several ways, including noncompetitive vs. competitive inhibitors, or intravenous vs. oral inhibitors. From a clinical standpoint, non-competitive inhibitors (such as abciximab) have longer biological half-lifes, more cross-reactivity with other cell-surface receptors, and higher dissociation constants (more permanent binding) than competitive inhibitors (eptifibatide, tirofiban), which may translate into more durable clinical efficacy (in terms of reducing ischemic complications) and less restenosis (possibly due to cross-reactivity with the vitronectin receptor). In TARGET, the only direct head-to-head comparison trial of different IIb/IIIa inhibitors, abciximab resulted in less death, MI, or urgent revascularization at 30 days in ACS patients undergoing PCI compared to tirofiban (abciximab 6.0% vs. tirofiban 9.3%); there was no difference in outcome for non-ACS patients. A randomized trial comparing abciximab to eptifibatide has not been performed. Answers: 1(b); 2(a); 3(b) 4. Which of the following statements about abciximab's actions are true: a. Blocks the GP IIb/IIIa receptor Make your selection before scrolling beyond this point Answer: The chimeric monoclonal antibody fragment c7E3 Fab (abciximab, ReoProTM) blocks platelet GP IIb/IIIa receptors, the vitronectin receptor on smooth muscle and endothelial cells, and the MAC-1 receptor on leukocytes. Interaction with these receptors may confer antiplatelet, antiproliferative (i.e., restenosis), and anti-inflammatory activity, respectively. Inhibition of clot retraction, factor XIII, and PAI-1; displacement of fibrinogen; and prolongation of the ACT may confer additional anticoagulant and thrombolytic activity unique to abciximab. (Answer: All) 5. Which statements about abciximab trial results are true: a. EPIC, EPILOG, EPISTENT, and CAPTURE demonstrated
significant reductions in the combined incidence of death, MI, and urgent
revascularization at 30 days Make your selection before scrolling beyond this point Answer: Abciximab has been studied in several large-scale, placebo-controlled randomized trials and is utilized in almost 50% of interventional procedures in the United States. Trials in PTCA (EPIC, EPILOG, CAPTURE), stent (EPISTENT), and acute MI (ADMIRAL, RAPPORT) have been completed. In EPIC, EPILOG, EPISTENT and CAPTURE, the primary endpoint was the combined incidence of death, MI, and urgent revascularization at 30 days; all demonstrated 35-57% relative risk reduction for abciximab, which was particularly notable in patients with unstable angina and acute MI. Although EPIC reported more bleeding complications with abciximab, EPILOG confirmed that low-dose weight adjusted heparin (70 u/kg to achieve ACT 200-250 sec) plus abciximab could significantly attenuate the risk of bleeding without sacrificing efficacy. Furthermore, the use of abciximab in high-risk PTCA patients in EPIC was extended to high and low-risk PTCA patients in EPILOG and to high and low-risk stent patients in EPISTENT. Importantly, EPIC continues to demonstrate sustained benefit of abciximab at 30-days, 6-months, and 3-years, with respect to the primary endpoint (death, MI, TLR) and with respect to the combined endpoint of death and MI. Similarly, EPISTENT reported sustained benefit at 6-months, as well as significant reduction in 1-year mortality with abciximab (1% vs. 2.4%). Angiographic restenosis was also lower in diabetics treated with abciximab than in diabetes not receiving abciximab. (Answer: a, b) 6. Which statements about abciximab dosing and adjunctive pharmacotherapy are true: a. All patients should receive standard aspirin therapy Make your selection before scrolling beyond this point Answer: All patients should receive standard aspirin therapy. The recommended dose of abciximab for percutaneous intervention is a 0.25 mg/kg IV bolus administered 10 minutes before intervention, followed by a continuous infusion of 0.125 µg/kg/min (to a maximum of 10 µg/kg/min) for 12 hours after intervention. The recommended heparin dose is 70 U/kg to achieve an ACT 200-250 sec; no additional heparin is used after intervention. Vascular sheaths should be removed when the ACT is 150-175 sec; there is no need to discontinue the abciximab infusion for sheath removal. When abciximab is administered after full dose heparinization (so-called "rescue ReoPro"), additional heparin should be used cautiously to reduce the risk of bleeding. (Answer: a, c) 7. Which statements about bleeding after abciximab are true: a. Standard-dose heparin, high ACT, and low body weight
increase the risk of bleeding Make your selection before scrolling beyond this point Answer: In most trials, major bleeding was defined as a drop in hemoglobin >5gm/dL, an absolute drop in hematocrit > 15%, or intracranial hemorrhage. Minor bleeding was defined as a drop in hemoglobin > 3gm/dL with evident blood loss or > 4 gm/dL in the absence of blood loss. In EPIC, EPILOG, and RAPPORT bleeding was more frequent with abciximab, standard dose heparin, and high ACT; acute MI, low body weight, longer procedural times, repeat PTCA, and failed intervention were independent predictors of bleeding. In contrast, EPILOG, CAPTURE, and EPISTENT, utilizing low-dose heparin, early sheath removal, and ACT 200-250 sec, reported no difference in major and minor bleeding for patients treated with abciximab or placebo. These studies suggest that in patients treated with abciximab, bleeding complications can be minimized by low-dose heparin (70 U/kg) to maintain the ACT 200-250 sec, early sheath removal, avoidance of venous sheaths, and fastidious post-procedure groin care. Importantly, patients treated with abciximab do not have a higher incidence of intracranial hemorrhage compared to placebo. (Answer: a, b) 8. All of the following statements about abciximab-induced thrombocytopenia are true except: a. The incidence of thrombocytopenia (<100,000/mm3)
is 15% Make your selection before scrolling beyond this point Answer: The incidence of thrombocytopenia (< 100,000/mm3) with abciximab is 2.6-5.2%. Unlike heparin-induced thrombocytopenia, abciximab-associated thrombocytopenia responds within days of discontinuing the drug, and will also respond promptly to platelet transfusion. Severe thrombocytopenia (< 50,000/mm3) after abciximab retreatment is 2-3 times more frequent than after first time use, and may not respond promptly to platelet transfusions. The incidence of human-anti-chimeric antibody (HACA) IgG antibodies is 6.5% in abciximab-treated patients, which may lead to immune thrombocytopenia after retreatment. HACA antibodies are specific for the murine epitope of the f(ab) antibody fragment, peak at 1-4 weeks after abciximab treatment, and decline over the next few months. The exact significance of HACA is unknown, but they appear to interfere with binding of abciximab to GP IIb/IIIa and to reduce its efficacy. An early study of readministration of abciximab in 500 patients reported a 3-fold higher incidence of severe thrombocytopenia than with initial administration; final recommendations regarding the use of readministration abciximab await further data. (Answer: c) Questions 9-13 list characteristics of thrombocytopenia due to abciximab, heparin, both or neither. For each characteristic below, choose one of the following: a. abciximab (ReoPro) 9. Onset within hours of exposure Make your selection before scrolling beyond this point Answers: 9(a); 10(a); 11(b); 12(b); 13(b)
14. Abciximab increases the risk of bleeding when used with: a. Aspirin Make your selection before scrolling beyond this point Answer: b, c, d
a. The dose of adjunctive heparin should be reduced Make your selection before scrolling beyond this point Answer: In IMPACT II and PURSUIT, the incidence of major bleeding was similar for eptifibatide and heparin. In contrast to abciximab, there is no need to reduce the heparin dose, there is no known immune response, and the incidence of thrombocytopenia is 2.8-3.2%. In PURSUIT, the incidence of severe thrombocytopenia (<50,000) was similar to placebo (0.6% vs. 0.4%). Eptifibatide should be discontinued in patients requiring emergency CABG; antiplatelet effects will resolve in 4-6 hours. Drug clearance is longer in patients with impaired renal function. (Answer: b, c) 16. Which statements about tirofiban (Aggrastat) are true: a. It is a small-molecule non-peptide competitive
antagonist of the GP IIb/IIIa receptor Make your selection before scrolling beyond this point Answer: Tirofiban (Aggrastat) is a synthetic, small-molecule nonpeptide competitive antagonist of GP IIb/IIIa. As with eptifibatide, it is rapidly reversible, highly selective for GP IIb/IIIa, and does not cross-react with the vitronectin receptor. (Answer: a, b)
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