Glycoprotein IIb/IIa inhibitors

1. Glycoprotein IIb/IIIa inhibitors Presented by Dr. Saurabh Patil Guide Dr. Shruti Bhide Date 28th September 2019 Venue Department of Pharmacology and Therapeutics, Seth G S Medical College and KEM Hospital, Parel, Mumbai

2. Mr. Rana 55/M c/o substernal pain, shortness of breath since 30 mins k/c/o HTN Smoking: 10 pack years

6. Myocardial Infarction

7. IV NTG Aspirin Heparin Eptifibatide (180 mcg/kg Loading) ↓ Chest pain persists ↓ Angiography ↓ 90% LAD block ↓ Angioplasty Myocardial Infarction ✓

13. IV NTG Aspirin Heparin Eptifibatide (180 mcg/kg Loading) ↓ Chest pain persists ↓ Angiography ↓ 90% LAD block ↓ Angioplasty Myocardial Infarction ✓ Clopidogrel during stenting ↓ Shifted to ward ↓ Hematoma at arterial access site in right thigh ↓ Stopped Eptifibatide, Pressure at hematoma site ↓ Hematoma resolved ↓ Discharged after 2 days

15. IV NTG Aspirin Heparin Eptifibatide (180 mcg/kg Loading) ↓ Chest pain persists ↓ Angiography ↓ 90% LAD block ↓ Angioplasty Myocardial Infarction ✓ Clopidogrel during stenting ↓ Shifted to ward ↓ Hematoma at arterial access site in right thigh ↓ Stopped Eptifibatide Pressure at hematoma site ↓ Hematoma resolved ↓ Discharged after 2 days

18. IV NTG Aspirin Heparin Eptifibatide (180 mcg/kg Loading) ↓ Chest pain persists ↓ Angiography ↓ 90% LAD block ↓ Angioplasty Myocardial Infarction ✓ Clopidogrel during stenting ↓ Shifted to ward ↓ Hematoma at arterial access site in right thigh ↓ Stopped Eptifibatide, Pressure at hematoma site ↓ Hematoma resolved ↓ Discharged after 2 days ? ? ? ?

19. Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic basis of disease (Ninth edition.)

21. Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and Cotran pathologic basis of disease (Ninth edition.) PDE cGMP Thrombin COX-1 TXA2

23. 2 1 3 4 5 Goodman, L. S., Brunton, L. L., Chabner, B., & Knollmann, B. C. (2011). Goodman & Gilman's pharmacological basis of therapeutics.

24. Platelet Aggregation Cascade

36. What is GP IIb/IIIa

37. What is GP IIb/IIIa Glycoprotein

38. What is GP IIb/IIIa Heterodimer Glycoprotein Golan, D. E. (2005). Principles of pharmacology: The pathophysiologic basis of drug therapy. Baltimore: Lippincott Williams & Wilkins.

39. What is GP IIb/IIIa Platelet

40. What is GP IIb/IIIa Platelet Platelet

41. What is GP IIb/IIIa Fibrinogen Platelet Platelet

46. What is GP IIb/IIIa Platelet Platelet Glanzmann Thrombasthenia

47. What is GP IIb/IIIa Skaik, Younis. (2015). Expression of the Recombinant Soluble Glycoprotein IIb: Lessons Learned and Future Directions. Global Journal of Hematology and Blood Transfusion. 2. 16-19. 10.15379/2408-9877.2015.02.02.03.

48. Which are GP IIb/IIIa Inhibitors?

49. Which are GP IIb/IIIa Inhibitors? Trigramin Barbourin Kistrin Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Neki, N.S. (2004). Platelet Glycoprotein IIb / IIIa Receptor Inhibitors – Role in Coronary Artery Disease. JIACM 2004; 5(3): 259-65

50. Which are GP IIb/IIIa Inhibitors? Trigramin Barbourin Kistrin Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban

51. Which are GP IIb/IIIa Inhibitors? Trigramin Barbourin Kistrin Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Synthetic Natural

56. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban

57. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Phase I Phase II Phase III

58. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Phase I Phase II Phase III ✓ ✓ ✓ ✓ ✓ Excess bleeding ✓ ✓ ✓ ✓ ✓ ✓

59. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Phase I Phase II Phase III ✓ ✓ ✓ (ongoing) ✓ ✓ ✓ ✓ ✓ ✓ Excess bleeding ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓

60. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Phase I Phase II Phase III ✓ ✓ ✓ ✓ (ongoing) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ No Efficacy Excess bleeding ✓ ✓ No Efficacy ✓ ✓ Excess mortality ✓ ✓ No Efficacy ✓ ✓ No Efficacy ✓ ✓ Discontinued ✓ ✓ Excess mortality

61. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban Phase I Phase II Phase III ✓ ✓ ✓ ✓ (ongoing) ✓ ✓ ✓ ✓ ✓ ✓ ✓ ✓ No Efficacy Excess bleeding ✓ ✓ No Efficacy ✓ ✓ Excess mortality ✓ ✓ No Efficacy ✓ ✓ No Efficacy ✓ ✓ Discontinued ✓ ✓ Excess mortality 1997 1998 1998

62. Fates of GP IIb/IIIa inhibitors Abciximab YM337 Eptifibatide Tirofiban Lamifiban Fradafiban Xemilofiban Orofiban Sibrafiban Lefradafiban Roxifiban Lotrafiban 1997 1998 1998

63. Abciximab Eptifibatide Tirofiban

64. Abciximab Eptifibatide Tirofiban

65. Chemistry Chimeric Hybrid Murine–human MAb Fab Fragment (50,000 Daltons) Cyclic heptapeptide (800 Daltons) Synthetic nonpeptide tyrosine analogue (500 Daltons) Dosing 250 mcg/kg IV (bolus) 180 mcg/kg IV (bolus) + 190 mcg/kg IV (bolus) (after 10 mins) 25 mcg/kg IV (bolus) Abciximab Eptifibatide Tirofiban

66. Chemistry Chimeric Hybrid Murine–human MAb Fab Fragment (50,000 Daltons) Cyclic heptapeptide (800 Daltons) Synthetic nonpeptide tyrosine analogue (500 Daltons) Dosing 250 mcg/kg IV (bolus) + 125 mcg/kg/min (12 hr infusion) 180 mcg/kg IV (bolus) + 190 mcg/kg IV (bolus) (after 10 mins) + 2 mcg/kg/min (24 hr infusion) 25 mcg/kg IV (bolus) + 0.15 mcg/kg/min (18 hr infusion) Half life Plasma T½ 30 minutes ____________ Plasma T½ 15 mins ____________ Plasma T½ 2 hrs ____________ Abciximab Eptifibatide Tirofiban

67. Dosing 250 mcg/kg IV (bolus) + 125 mcg/kg/min (12 hr infusion) 190 mcg/kg IV (bolus) (after 10 mins) + 2 mcg/kg/min (24 hr infusion) 25 mcg/kg IV (bolus) + 0.15 mcg/kg/min (18 hr infusion) Half life Plasma T½ 30 minutes ____________ Platelet-bound T½ in Days Plasma T½ 15 mins ____________ Platelet-bound T ½ in Seconds Plasma T½ 2 hrs ____________ Platelet-bound T ½ in Seconds Return of platelet function 12 hrs 4 hrs 4 hrs Reversible with platelet Yes No No Abciximab Eptifibatide Tirofiban

68. (12 hr infusion) (24 hr infusion) (18 hr infusion) Half life Plasma T½ 30 minutes ____________ Platelet-bound T½ in Days Plasma T½ 15 mins ____________ Platelet-bound T ½ in Seconds Plasma T½ 2 hrs ____________ Platelet-bound T ½ in Seconds Return of platelet function 12 hrs 4 hrs 4 hrs Reversible with platelet transfusion Yes No No Self reversibility No Yes Yes Excretion Unknown Renal clearance Renal clearance PCI PCI Abciximab Eptifibatide Tirofiban

69. with platelet transfusion Yes No No Self reversibility No Yes Yes Excretion Unknown Renal clearance Renal clearance Indication PCI ACS PCI ACS ACS Contra- indication Hypersensitivity (Murine proteins) Bleeding tendency Neuraxial catheter in situ Uncontrolled Hypertension On dialysis Neuraxial catheter in situ h/o ↓ Platelets Neuraxial catheter in situ Immunogenicity Abciximab Eptifibatide Tirofiban

70. platelet transfusion Yes No No Self reversibility No Yes Yes Excretion Unknown Renal clearance Renal clearance Indication PCI ACS PCI ACS ACS Contra- indication Hypersensitivity (Murine proteins) Bleeding tendency Neuraxial catheter in situ Uncontrolled Hypertension On dialysis Neuraxial catheter in situ h/o ↓ Platelets Neuraxial catheter in situ Adverse Immunogenicity Bleeding Bleeding Bleeding Abciximab Eptifibatide Tirofiban

71. Contra- indication Bleeding tendency Neuraxial catheter in situ Hypertension On dialysis Neuraxial catheter in situ h/o ↓ Platelets Neuraxial catheter in situ Adverse effect Immunogenicity Bleeding ↓ Platelets Bradycardia Bleeding ↓ Platelets Bleeding ↓ Platelets Pleiotropic effects Binds to Vitronectin receptor - - Abciximab Eptifibatide Tirofiban

72. Contra- indication Bleeding tendency Neuraxial catheter in situ Hypertension On dialysis Neuraxial catheter in situ h/o ↓ Platelets Neuraxial catheter in situ Adverse effect Immunogenicity Bleeding ↓ Platelets Bradycardia Bleeding ↓ Platelets Bleeding ↓ Platelets Pleiotropic effects Binds to Vitronectin receptor - - Abciximab Eptifibatide Tirofiban Discontinue + Platelet Transfusion Tanzilli G, Sordi M, Arrivi A, Mangieri E, Scappaticci M. Acute profound abciximab induced thrombocytopenia: a correct management of a methodological error. Case Reports. 2009 Oct 5;2009(oct05 1):bcr1220081381–bcr1220081381. Discontinue + Supportive care Discontinue + Supportive care

75. Neuraxial catheter in situ Neuraxial catheter in situ Neuraxial catheter in situ Adverse effect Immunogenicity Bleeding ↓ Platelets Bradycardia Bleeding ↓ Platelets Bleeding ↓ Platelets Pleiotropic effects Binds to Vitronectin receptor - - Abciximab Eptifibatide Tirofiban Golan, D. E. (2005). Principles of pharmacology: The pathophysiologic basis of drug therapy. Baltimore: Lippincott Williams & Wilkins.

76. effect ↓ Platelets Bradycardia ↓ Platelets ↓ Platelets Pleiotropic effects Binds to Vitronectin receptor - - Abciximab Eptifibatide Tirofiban

77. effect ↓ Platelets Bradycardia ↓ Platelets ↓ Platelets Pleiotropic effects Binds to Vitronectin receptor - - Abciximab Eptifibatide Tirofiban Current Guidelines Sr. No. Drug Indication Recommendation Class 1 Use of Abciximab Primary PCI Class IIa – Level A 2 Use of Abciximab intracoronary inj. Primary PCI Class IIb – Level B

78. Current Guidelines Sr. No. Drug Indication Recommendation Class 1 Use of Abciximab Primary PCI Class IIa – Level A 2 Use of Abciximab intracoronary inj. Primary PCI Class IIb – Level B 3 Use of Eptifibatide / Tirofiban Primary PCI Class IIa – Level B 4 Discontinuation of GP IIb/IIIa inhibitor Before Urgent CABG Class I – Level B O’Gara P, Kushner F, Ascheim D, Casey D, Chung M, de Lemos J et al. 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction. Circulation. 2013;127(4).

79. Sr. No. Drug Indication Recommendation Class 1 Use of Abciximab Primary PCI Class IIa – Level A 2 Use of Abciximab intracoronary inj. Primary PCI Class IIb – Level B 3 Use of Eptifibatide / Tirofiban Primary PCI Class IIa – Level B 4 Discontinuation of GP IIb/IIIa inhibitor Before Urgent CABG Class I – Level B Current Guidelines

81. Current trends Published articles 0 20 40 60 80 100 120 “GP IIb/IIIa inhibitors”

84. Current trends Published articles

85. Current trends Published articles “Abciximab” 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

86. Current trends Published articles “Eptifibatide” 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

87. Current trends Published articles “Tirofiban” 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

88. 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

89. “Abciximab” 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 1994 EPIC 1. Abciximab 2. Placebo 1997 EPILOG 1. Abciximab + Low dose heparin 2. Abciximab + Standard dose heparin 3. Placebo + Standard dose heparin 1997 CAPTURE 1. Abciximab 2. Placebo 1998 EPISTENT 1. Stenting + Placebo 2. Stenting + Abciximab 3. Balloon angioplasty + Abciximab 2001 GUSTO IV-ACS 1. Placebo + Aspirin + Heparin 2. Abciximab (24 h) + Aspirin + Heparin 3. Abciximab (48 h) + Aspirin + Heparin 2001 TARGET 1. Tirofiban 2. Abciximab 2004 ISAR REACT 1 1. Abciximab 2. Placebo 2011 TENACITY 1. Tirofiban (high dose) 2. Abciximab

97. “Eptifibatide” 1997 IMPACT-II 1. Eptifibatide 2. Placebo 1998 PURSUIT 1. Eptifibatide 2. Placebo 2000 ESPRIT 1. Eptifibatide 2. Placebo 2009 EARLY-ACS 1. Eptifibatide before angiography 2. Eptifibatide after angiography 2012 SAVI-PCI 1. Eptifibatide 2. Long Tirofiban (high dose) 3. Short Tirofiban (high dose) 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

104. “Tirofiban” 1997 RESTORE 1. Tirofiban 2. Placebo 1998 PRISM 1. Tirofiban + Aspirin 2. Aspirin 1998 PRISM-PLUS 1. Tirofiban 2. Heparin 3. Tirofiban + Heparin 2001 TARGET 1. Tirofiban 2. Abciximab 2011 TENACITY 1. Tirofiban (high dose) 2. Abciximab 2012 SAVI-PCI 1. Eptifibatide 2. Long Tirofiban (high dose) 3. Short Tirofiban (high dose) 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019

110. Current fate Mostly replaced in practice due to other classes of drugs especially ADP receptor pathway inhibitors (Prasugrel, Ticagrelor)

111. OPEN HOUSE

Glycoprotein IIb/IIa inhibitors

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