Gp2b3a

trails on GP2b3a inhibitors

1. Drugs in the Group Abciximab Tirofiban Eptifibatide

2. Antiplatelet therapy with intravenous GP IIb/IIIa inhibitors has been evaluated in patients with acute coronary syndrome (ACS) and in those undergoing intracoronary stent implantation. Dual oral antiplatelet therapy with aspirin and a platelet P2Y 12  receptor blocker has decreased the role of GP IIb/IIIa therapy in these settings.

3. THE PLATELET GP IIB/IIIA RECEPTOR Platelet activation and aggregation is preceded by rolling, tethering, transient adhesion, and firm adhesion, and occurs following exposure to several biochemical and mechanical stimuli . The ability of platelets to adhere to abnormal surfaces and aggregate is mediated by surface membrane glycoprotein (GP) receptors that can be expressed in greater numbers and assume a more ligand-binding conformation upon platelet activation The platelet GP IIb/IIIa receptor is of particular interest because of its central role in platelet adhesion and aggregation. Following platelet activation, GP IIb/IIIa undergoes a conformational change, rendering it competent to bind protein ligands, including Von Willebrand factor in general and fibrinogen in particular

4. ABCIXIMAB  Fab fragment of the chimeric human-murine monoclonal antibody 7E3

5. Pharmacokinetics and pharmacodynamics Free plasma concentrations of abciximab decrease rapidly with an initial half-life of less than 10 minutes and a second phase half-life of 30 minutes, owing to rapid binding to the platelet glycoprotein (GP) IIb/IIIa receptor Platelet function generally recovers over the course of 48 hours abciximab remains in the circulation for up to 10 days in the platelet-bound state .  Upon completion of a constant infusion, free plasma concentrations fall rapidly over the next six hours then decline at a slower rate

6. doses Percutaneous coronary intervention (PCI):  IV: 0.25 mg/kg bolus administered 10 to 60 minutes prior to start of PCI followed by an infusion of 0.125 mcg/kg/minute (maximum: 10 mcg/minute) for 12 hours Unstable angina/non-ST-elevation MI (UA/NSTEMI) unresponsive to conventional medical therapy with planned PCI within 24 hours:  IV: 0.25 mg/kg bolus followed by an 18- to 24-hour infusion of 10 mcg/minute, concluding 1 hour after PCI.

7. ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) (off-label use) (ACCF/AHA [O'Gara 2013]): Loading dose: 0.25 mg/kg bolus administered at the time of PCI Maintenance infusion: 0.125 mcg/kg/minute (maximum: 10 mcg/minute) continued for up to 12 hours Intracoronary (off-label route): 0.25 mg/kg bolus administered directly to the site of the infarct lesion; may be followed with an intravenous maintenance infusion if refractory intraprocedural thrombotic complications occur (Stone 2012)

8. TIROFIBAN Nonpeptide inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor and interferes with platelet aggregation.

9. dose Unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI):   IV: Loading dose: 25 mcg/kg administered over 5 minutes or less; Maintenance infusion: 0.15 mcg/kg/minute continued for up to 18 hours Percutaneous coronary intervention (PCI):  IV: Loading dose: 25 mcg/kg administered over 5 minutes or less at the time of PCI; Maintenance infusion: 0.15 mcg/kg/minute continued for up to 18 hours (ACCF/AHA/SCAI [Levine 2011]; Valgimigli 2004)

10. Stable ischemic heart disease (high-risk features) undergoing elective PCI (off-label use):   Loading dose: 25 mcg/kg administered over 5 minutes or less at the time of PCI; Maintenance infusion: 0.15 mcg/kg/minute; was continued for up to 48 hours in the clinical trial (ACCF/AHA/SCAI [Levine 2011]; Valgimigli 2004).  Note : Reserve for patients who were not pretreated with clopidogrel or who are undergoing elective PCI with stent implantation with adequate clopidogrel pretreatment (ACCF/AHA/SCAI [Levine 2011]). ST-elevation myocardial infarction (STEMI) undergoing primary PCI (off-label use):   IV Loading dose: 25 mcg/kg administered over 5 minutes or less at the time of PCI; Maintenance infusion: 0.15 mcg/kg/minute in combination with heparin or bivalirudin in selected patients; was continued for 18-24 hours in clinical trials (ACCF/AHA [O’Gara 2013]; ACCF/AHA/SCAI [Levine 2011]; Valgimigli 2008; Van’t Hof 2008)

11. EPTIFIBATIDE   Eptifibatide (INTEGRILIN) is a cyclic heptapeptide inhibitor of GP IIb-IIIa, with an active pharmacophore that is derived from the structure of barbourin, a GP IIb-IIIa inhibitor from the venom of the south-eastern pigmy rattlesnake. Like barbourin, eptifibatide is a specific and robust inhibitor of the GP IIb-IIIa receptor function, having a low affinity for other integrins and strongly preventing platelet aggregation. 

12. PHARMACOLOGY The plasma half-life of  Eptifibatide  is 10 to 15 minutes and clearance is predominantly renal (75 percent) and hepatic (25 percent). The antiplatelet effect has a rapid onset of action and is rapidly reversible. Boluses of 180 or 135 µg/kg produce greater than 80 percent inhibition of adenosine diphosphate (ADP)-mediated platelet aggregation within 15 minutes of administration in more than 75 percent of patients.

13. dose Acute coronary syndrome:   IV: 180 mcg/kg bolus (maximum: 22.6 mg) administered as soon as possible following diagnosis, followed by a continuous infusion of 2 mcg/kg/minute (maximum: 15 mg/hour) until hospital discharge or initiation of CABG surgery (discontinue ≥2 to 4 hours before surgery (ACCF/AHA [Hillis, 2011]), up to 72 hours. If PCI performed during initial 72 hours, maintain continuous infusion at the time of PCI and continue until hospital discharge or for up to 18 to 24 hours, whichever comes first (total infusion time ≤96 hours). Concurrent aspirin and heparin therapy (target aPTT 50 to 70 seconds) are recommended. 

14. Percutaneous coronary intervention (PCI) with or without stenting:   IV: 180 mcg/kg bolus (maximum: 22.6 mg) administered immediately before the initiation of PCI, followed by a continuous infusion of 2 mcg/kg/minute (maximum: 15 mg/hour). A second 180 mcg/kg bolus (maximum: 22.6 mg) should be administered 10 minutes after the first bolus. Infusion should be continued until hospital discharge or for up to 18 to 24 hours, whichever comes first; shorter infusion durations ( ie , <2 hours) may be considered for nonemergent uncomplicated PCI in patients adequately pretreated with clopidogrel (Fung, 2007). Preprocedural aspirin and heparin therapy (ACT 200 to 250 seconds during PCI) and daily aspirin are recommended. Heparin infusion after PCI is discouraged. In patients who undergo CABG surgery, discontinue infusion ≥2 to 4 hours prior to surgery (ACCF/AHA [Hillis, 2011]).  Primary percutaneous coronary intervention (PCI) during ST-elevation myocardial infarction with or without stenting or pretreatment with clopidogrel (off-label use):   IV: Bolus of 180 mcg/kg (maximum: 22.6 mg) administered at the time of PCI, followed by a continuous infusion of 2 mcg/kg/minute (maximum: 15 mg/hour) in combination with heparin or bivalirudin. A second 180 mcg/kg bolus (maximum: 22.6 mg) should be administered 10 minutes after the first bolus (ACCF/AHA [O'Gara, 2013]). Infusion was continued for 24 hours in one study ( Zeymer , 2010)

15. Guidelines

16. STEMI

17. NSTEMI

18. TRAILS INVOVLED IN THE ABOVE LEVEL OF EVIDENCE

19. abciximab

20. ACS Patients undergoing pci A number of randomized trials were performed with  abciximab in patients undergoing percutaneous coronary intervention (PCI) before the routine practice of stent insertion. In a meta-analysis of over 5400 (predominantly) acute coronary syndrome (ACS) patients enrolled in the EPIC , EPILOG , RAPPORT, EPISTENT , and CAPTURE trials who underwent PTCA, abciximab significantly reduced the 30-day rate of death and myocardial infarction (MI) (hazard ratio 0.52, 95% CI 0.41-0.65).

21. EPIC INVESTIGATORS Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty - N Engl J Med. 1994;330(14):956.  Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months - Lancet. 1994;343(8902):881 Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention . - JAMA. 1997;278(6):479.

22. EPILOG Investigators Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization - N Engl J Med. 1997;336(24):1689.  Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab: one-year outcome in the EPILOG trial. Evaluation in PTCA to Improve Long-term Outcome with abciximab GP IIb/IIIa blockade. - Circulation. 1999;99(15):1951

23. RAPPORT Trail Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators - Circulation. 1998;98(8):734.

24. CAPTURE investigators Randomized trial of a GPIIb /IIIa platelet receptor blocker in refractory unstable angina. European Cooperative Study Group. - Circulation. 1994;89(2):596 Assessment of coronary angiograms prior to and after treatment with abciximab, and the outcome of angioplasty in refractory unstable angina patients. Angiographic results from the CAPTURE trial. - Eur Heart J. 1999;20(21):1572 Reduction of recurrent ischemia with abciximab during continuous ECG-ischemia monitoring in patients with unstable angina refractory to standard treatment (CAPTURE). - Circulation. 1998;98(14):1358.  Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators. - N Engl J Med. 1999;340(21):1623.  Soluble CD40 ligand in acute coronary syndromes. - N Engl J Med. 2003;348(12):1104. 

25. Outcomes after either  abciximab or placebo were evaluated in several randomized trials of patients with ST-elevation MI (STEMI) undergoing primary PCI with (primarily) stent placement, including RAPPORT , ADMIRAL , ISAR-2 , CADILLAC , and ACE . In a meta-analysis of these trials, abciximab was associated with significant reductions in mortality at 30 days (2.4 versus 3.4 percent with placebo) and 6 to 12 months (4.4 versus 6.2 percent) and in reinfarction at 30 days (1.0 versus 1.9 percent). In addition, there was no increase in bleeding. This analysis provided support for the benefit of abciximab as adjunctive therapy to reduce acute ischemic events among patients undergoing primary PCI with stenting. STEMI patients undergoing PCI with stenting

26. ADMIRAL Investigators Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. - N Engl J Med. 2001;344(25):1895. Three-year duration of benefit from abciximab in patients receiving stents for acute myocardial infarction in the randomized double-blind ADMIRAL study. - Eur Heart J. 2005;26(23):2520. Epub 2005 Oct 25

27. ISAR-2 Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. -- J Am Coll Cardiol . 2000;35(4):915

28. CADILLAC Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. - N Engl J Med. 2002;346(13):957.

29. ACE trial A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. - J Am Coll Cardiol . 2003;42(11):1879

30. In contrast to the benefit of  abciximab observed among patients with ACS, including those with STEMI. two trials (EPISTENT and ISAR-REACT) included some patients with stable coronary artery disease undergoing PCI with stenting and came to different conclusions Stable patients

31. EPISTENT Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. - Lancet. 1998;352(9122):87 At 63 hospitals in the USA and Canada, 2399 patients with ischaemic heart disease and suitable coronary-artery lesions were randomly assigned stenting plus placebo (n=809), stenting plus abciximab, a IIb/IIIa inhibitor (n=794), or balloon angioplasty plus abciximab (n=796). Platelet glycoprotein-IIb/IIIa blockade with abciximab substantially improves the safety of coronary-stenting procedures. Balloon angioplasty with abciximab is safer than stenting without abciximab.

32. ISAR-REACT trial A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel . - N Engl J Med. 2004;350(3):232 2159 patients with coronary artery disease who underwent a percutaneous coronary intervention: 1079 patients were randomly assigned in a double-blind manner to receive abciximab and 1080 patients to receive placebo. All patients were pre-treated with a 600-mg dose of clopidogrel at least two hours before the procedure. The primary end point of the trial was the composite of death, myocardial infarction, and urgent target-vessel revascularization within 30 days after randomization. data suggest that in patients at low-to-intermediate risk who undergo elective percutaneous coronary intervention after pretreatment with a high loading dose of clopidogrel , abciximab is associated with no clinically measurable benefit within the first 30 days.

33. Patients not undergoing reperfusion

34. GUSTO IV-ACS Investigators Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial. - Lancet. 2001;357(9272):1915 7800 patients who were admitted to hospital with chest pain and either ST-segment depression or raised troponin T or I concentrations. 2598 were randomly assigned placebo, 2590 an abciximab bolus and 24 h infusion, and 2612 an abciximab bolus and 48 h infusion; all patients received aspirin and either unfractionated or low-molecular-weight heparin. The lack of benefit from treatment with abciximab was consistent in most subgroups investigated; in particular, no benefit was seen in patients with raised cardiac troponin T or I concentrations at enrolment, although these patients did have a strongly increased risk of subsequent events this study indicates that abciximab is not beneficial as first-line medical treatment in patients admitted with acute coronary syndromes.

35. tirofiban

36. UA/NSTEMI patients undergoing PCI Several trials compared tirofiban  (bolus plus continuous infusion) with placebo or with heparin in patients with unstable angina (UA) or non-ST elevation myocardial infarction (NSTEMI) scheduled to undergo percutaneous coronary intervention (PCI) without stent insertion, and in whom P2Y 12  receptor blockers were  not  routinely used. RESTORE  trial PRISM-PLUS trial ADVANCE trial

37. RESTORE TRAIL Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. The RESTORE Investigators. Randomized Efficacy Study of Tirofiban for Outcomes and Restenosis. - Circulation. 1997;96(5):1445 A randomized, double-blind, placebo-controlled trial of tirofiban in patients undergoing coronary interventions (balloon angioplasty or directional atherectomy) within 72 hours of presentation with an acute coronary syndrome (unstable angina pectoris or acute myocardial infarction). In patients undergoing coronary angioplasty for acute coronary syndromes, tirofiban protects against early adverse cardiac events related to thrombotic closure. At 30 days, however, the reduction in adverse cardiac events was no longer statistically significant. The bleeding observed with tirofiban was not statistically different from that observed with placebo.

38. PRISM TRAIL Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. PRISM Study Investigators. Platelet Receptor Inhibition in Ischemic Syndrome Management. - Lancet. 1999;354(9192):1757.  2222 patients of the Platelet Receptor Inhibition in Ischemic Syndrome Management study with coronary artery disease and who had had chest pain in the previous 24 h. All patients received aspirin and were randomly assigned treatment with tirofiban or heparin. We took baseline measurements of troponin I and troponin T. We recorded death, myocardial infarction, or recurrent ischaemia after 48 h infusion treatment and at 7 days and 30 days. Troponin I and troponin T reliably identified high-risk patients with acute coronary syndromes, managed medically and by revascularisation, who would benefit from tirofiban.

39. PRISM – PLUS TRAIL Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. - N Engl J Med. 1998;338(21):1488 Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators A total of 1915 patients were randomly assigned in a double-blind manner to receive tirofiban, heparin, or tirofiban plus heparin. When administered with heparin and aspirin, the platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban was associated with a lower incidence of ischemic events in patients with acute coronary syndromes than in patients who received only heparin and aspirin.

40. ADVANCE trial The additive value of tirofiban administered with the high-dose bolus in the prevention of ischemic complications during high-risk coronary angioplasty: the ADVANCE Trial. - J Am Coll Cardiol . 2004;44(1):14.  The use of tirofiban, when administered at HDB, is safe and significantly reduces the incidence of ischemic/thrombotic complications during high-risk PCI.

41. ACS patients treated medically Two studies have evaluated ACS patients managed with medical therapy. TETAMI trial PRISM trial

42. TETAMI trial  The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial. - J Am Coll Cardiol . 2003;42(8):1348 A total of 1224 patients were enrolled in 91 centers in 14 countries between July 1999 and July 2002. Patients with STEMI ineligible for reperfusion were randomized to enoxaparin, enoxaparin plus tirofiban, UFH, or UFH plus tirofiban. All patients received oral aspirin This study did not show that enoxaparin significantly reduced the 30-day incidence of death, reinfarction, and recurrent angina compared with UFH in non- reperfused STEMI patients. However, enoxaparin appears to have a similar safety and efficacy profile to UFH and may be an alternative treatment. Additional therapy with tirofiban did not appear beneficial

43. PRISM TRIAL A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. - N Engl J Med. 1998;338(21):1498. Tirofiban was generally well tolerated and, as compared with heparin, reduced ischemic events during the 48-hour infusion period, during which revascularization procedures were not performed. The incidence of refractory ischemia and myocardial infarction was not reduced at 30 days, but mortality was lower among the patients given tirofiban. Platelet inhibition with aspirin plus tirofiban may have a role in the management of unstable angina

44. STEMI patients undergoing primary PCI   TIGER-PA pilot, On- TIme On-TIME 2 

45. TIGER- PA (PILOT) TRIAL Adjunctive platelet glycoprotein IIb/IIIa receptor inhibition with tirofiban before primary angioplasty improves angiographic outcomes: results of the TIrofiban Given in the Emergency Room before Primary Angioplasty (TIGER-PA) pilot trial - Circulation. 2003;107(11):1497.  The TIGER-PA pilot trial was a single- center randomized study to evaluate the safety, feasibility, and utility of early tirofiban administration before planned primary angioplasty in patients presenting with acute myocardial infarction. A total of 100 patients presenting with acute myocardial infarction were randomized to either early administration of tirofiban in the emergency room or later administration in the catheterization laboratory This pilot study suggests that early administration of tirofiban improves angiographic outcomes and is safe and feasible in patients undergoing primary angioplasty for acute myocardial infarction.

46. ON-TIME TRAIL Facilitation of primary coronary angioplasty by early start of a glycoprotein 2b/3a inhibitor: results of the ongoing tirofiban in myocardial infarction evaluation (On-TIME) trial. - Eur Heart J. 2004;25(10):837. From June 2001 to November 2002, 507 patients with acute myocardial infarction, who were transferred to a PCI centre, were randomised to early, pre-hospital initiation of Tirofiban (Early) or to initiation in the catheterisation laboratory (Late). Early initiation of Tirofiban did not improve initial TIMI 3 flow of the IRV significantly. Despite a better patency (TIMI 2 or 3 flow), a lower prevalence of thrombus or fresh occlusion and a better myocardial perfusion in the infarct-related region pre-PCI, no beneficial effect on post-PCI angiographic or clinical outcome was found, as compared to initiation of Tirofiban in the catheterisation laboratory.

47.  (On-TIME) 2 investigators Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial - Lancet. 2008;372(9638):537. a double-blind, randomised, placebo-controlled trial in 24 centres in the Netherlands, Germany, and Belgium. Between June 29, 2006, and Nov 13, 2007, 984 patients with STEMI who were candidates to undergo PCI were randomly assigned to either high-bolus dose tirofiban (n=491) or placebo (N=493) in addition to aspirin (500 mg), heparin (5000 IU), and clopidogrel (600 mg). Randomisation was by blinded sealed kits with study drug, in blocks of four. The primary endpoint was the extent of residual ST-segment deviation 1 h after PCI. Analysis was by intention to treat. The trial is registered, number ISRCTN06195297.

48. FINDINGS 936 (95%) patients were randomly assigned to treatment after a prehospital diagnosis of myocardial infarction in the ambulance. Median time from onset of symptoms to diagnosis was 76 min (IQR 35-150). Mean residual ST deviation before PCI (10.9 mm [SD 9.2]vs 12.1 mm [9.4], p=0.028) and 1 h after PCI (3.6 mm [4.6]vs 4.8 mm [6.3], p=0.003) was significantly lower in patients pre-treated with high-bolus dose tirofiban than in those assigned to placebo. The rate of major bleeding did not differ significantly between the two groups (19 [4%]vs 14 [3%]; p=0.36).

49. INTERPRETATION Our finding that routine prehospital initiation of high-bolus dose tirofiban improved ST-segment resolution and clinical outcome after PCI, emphasises that further platelet aggregation inhibition besides high-dose clopidogrel is mandated in patients with STEMI undergoing PCI.

50. On-TIME 2 investigators Effect of early, pre-hospital initiation of high bolus dose tirofiban in patients with ST-segment elevation myocardial infarction on short- and long-term clinical outcome. - J Am Coll Cardiol . 2010;55(22):2446.  The On-TIME 2 trial consisted of 2 phases: an open-label phase, followed by a double-blind, placebo-controlled phase. STEMI patients were randomized to either HBD tirofiban or no tirofiban (phase 1) or placebo (phase 2) in addition to aspirin, heparin, and high-dose clopidogrel . The protocol pre-specified a pooled analysis of the 2 study phases to assess the incidence of major adverse cardiac events at the 30-day follow-up and on total mortality at the 1-year follow-up. Early, pre-hospital initiation of HBD tirofiban, in addition to high-dose clopidogrel , improves the clinical outcome after primary percutaneous coronary intervention in patients with STEMI. (Ongoing 2b/3a inhibition In Myocardial infarction Evaluation; ISRCTN06195297).

51. EPTIFIBATIDE

52. ACS patients IMPACT-II trial PURSUIT

53. IMPACT-II trial Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. ( Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II.) - Lancet. 1997;349(9063):1422.  A double-blind, placebo-controlled trial at 82 centres in the USA, enrolling 4010 patients undergoing elective, urgent, or emergency coronary intervention. Patients were assigned one of three treatments: placebo (n = 1328), a bolus of 135 micrograms/kg eptifibatide followed by an infusion of 0.5 microgram kg-1 min-1 for 20-24 h (n = 1349), or 135 micrograms/kg eptifibatide bolus with a 0.75 microgram kg-1 min-1 infusion (n = 1333).

54. In the 135/0.5 group, treatment with eptifibatide during coronary intervention reduced rates of early abrupt closure and ischaemic events at 30 days. Non-significant differences were seen with the 135/0.75 regimen. The doses studied thus appear to be at the low end of the efficacy-response curve. Further investigation to refine eptifibatide dosing during coronary intervention is warranted

55. PURSUIT TRAIL investigators Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. - - N Engl J Med. 1998;339(7):436. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Investigators  

56. Patients who had presented with ischemic chest pain within the previous 24 hours and who had either electrocardiographic changes indicative of ischemia (but not persistent ST-segment elevation) or high serum concentrations of creatine kinase MB isoenzymes were enrolled in the study. They were randomly assigned, in a double-blind manner, to receive a bolus and infusion of either eptifibatide or placebo, in addition to standard therapy, for up to 72 hours (or up to 96 hours, if coronary intervention was performed near the end of the 72-hour period). A total of 10,948 patients were enrolled between November 1995 and January 1997. Inhibition of platelet aggregation with eptifibatide reduced the incidence of the composite end point of death or nonfatal myocardial infarction in patients with acute coronary syndromes who did not have persistent ST-segment elevation.

57. PURSUIT Investigators Early percutaneous coronary intervention, platelet inhibition with eptifibatide, and clinical outcomes in patients with acute coronary syndromes. - Circulation. 2000;101(7):751.  In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (<72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) (P=0.001), MI preceded early PCI. Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively.

58. Stable patients ESPRIT trial

59. ESPRIT TRAIL Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial. - Lancet. 2000;356(9247):2037 ESPRIT Investigators. (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy ) . ESPRIT is a randomised, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting. 2064 patients undergoing stent implantation in a native coronary artery. Immediately before percutaneous coronary intervention, patients were randomly allocated to receive eptifibatide, given as two 180 microg/kg boluses 10 min apart and a continuous infusion of 2.0 microg/kg/min for 18-24 h, or placebo, in addition to aspirin, heparin, and a thienopyridine.

60. The trial was terminated early for efficacy. Routine glycoprotein IIb/IIIa inhibitor pre-treatment with eptifibatide substantially reduces ischaemic complications in coronary stent intervention and is better than a strategy of reserving treatment to the bailout situation.