Newer anti-platelets final.

PG Level

1. Dr.RENJU.S.RAVI MD NEWER ANTI-PLATELETS

2. Thrombosis is defined as “ Hemostasis in the wrong place ” Thrombosis is the formation of an unwanted clot within a blood vessel - the most common abnormality of hemostasis It is a major cause of morbidity and mortality morbidity and mortality in a wide range of arterial and venous diseases and patient population

3. Hemostasis and thrombosis primarily involve the interplay among three factors Vessel wall Coagulation proteins Platelets

4. PRIMARY HEMOSTASIS SECONDARY HEMOSTASIS

5. PLATELET PATHOPHYSIOLOGY platelets produced per day Anucleate cells Source of chemokines, cytokines that are preformed and stored as granules Activated platelets synthesize TXA2  

6. Pathophysiology of the Thrombus

7. ANTI-THROMBOTIC DRUGS

8. USES OF ANTIPLATELET DRUGS IN THE MANAGEMENT OF THROMBOTIC DISEASES Acute coronary syndrome UA/STEMI/NSTEMI Coronary artery disease Stroke Peripheral vascular disease Venous Thromboembolism Atrial fibrillation

9. ANTI-PLATELET DRUGS

10. Bleeding risk Thrombotic risk Will any drug ever prevent thrombosis without causing bleeding ?

11. NEWER ANTI-PLATELET AGENTS

12. PGI 2 Naturally occurring potent vasodilator and inhibitor of platelet aggregation. Inhibit platelet aggregation by stimulating adenylcyclase increasing cAMP levels in platelets Prostacyclins ( Epoprostenol )-used during haemodialysis or cardiopulmonary bypass, intermittent claudication

13. PHOSPHODIESTERASE ANTAGONISTS CILOSTAZOLE

14. P2Y 12 INHIBITORS ADP receptors P2Y 1 and P2Y 12 subtypes GPCR Both needed for aggregation – P2Y 12 pathway plays a principal role ADP RECEPTOR ANTAGONIST

15. Vasodilator stimulated phosphoprotein

16. TICAGRELOR Oral drug Non- thienopyridine - reversible inhibitor Binding site different from ADP -allosteric antagonist Does not require metabolic activation Maximum levels of both the drug and platelet inhibition occur about two hours after Loading dose -180 mg - Maintenance dose of 90 mg twice a day

17. Advantage of not requiring metabolism by the CYP450 - minimizes the potential for drug- drug interactions ( e.g., proton pump inhibitors and clopidogrel ) ELINOGREL Reversible antagonist Oral or parenteral This unique dual formulation provides the potential benefit for smooth transition from short term intravenous to long term oral antiplatelet therapy More effective at inhibiting platelet activation by lower, rather than higher, concentrations of ADP Maximum platelet inhibition occurs at 20 minutes Under PHASE III trial

18. CANGRELOR Rapid onset and offset of action – iv route Ultra-short half life 3-6 minutes Infusion of 4 μ g/kg per minute peak inhibition in 15 minutes - Rapid offset, with in 60 minutes >90% platelet inhibition More desirable for elective treatment of stenotic coronary arteries, high risk acute coronary syndromes treated with immediate coronary stenting, and for bridging those surgery patients who require P2Y12 inhibition Under PHASE III trial

19. Limitations of current therapies include Weak inhibition of platelet function (Eg. aspirin), Blockade of only one pathway of ADP-mediated signaling (Eg. clopidogrel), Slow onset of action Interpatient response variability with poor inhibition of platelet function in some patients

20. GPIIa / IIIb INHIBITORS It’s a platelet surface integrin Designated as α II b β3 Main use: Percutaneous Intervention (PCI) Limited efficacy after Myocardial Infarction

21. ABCIXIMAB EPTIFIBATIDE TIROFIBAN Molecule Fab fragment - chimeric Cyclic peptide Non peptide For GPIIa / IIIb Non specific Specific Specific Half-life Short -10 – 30mts 2.5 hrs 2 hrs Adverse effects Hge Thrombocytopenia Expensive Hge Thrombocytopenia Hge Thrombocytopenia

22. ABCIXIMAB It also binds to the vitronectin receptor on platelets, vascular endothelial cells, and smooth muscle cells. (Vitronectin is a GP present in serum and in matrix. It promotes Adhesion)

23. ORAL GPIIa / IIIb INHIBITORS XEMILOFIBAN Prodrug Non-peptide   Phase III study tested the hypothesis that chronic (up to 6 month) oral blockade of the GP IIb / IIIa receptor would provide both acute and ongoing protection from death, myocardial infarction, and the need for urgent revascularization

24. OTHER ORAL GPIIa / IIIb INHIBITORS Orbofiban – PHASE III Lotrafiban – PHASE III Sibrafiban

25. TRIPLE ANTI-PLATELET THERAPY Based on IV GPIIb / IIIa inhibitors is more effective than aspirin-based dual therapy in reducing vascular events, MI and death in patients with acute coronary syndromes (STEMI and NSTEMI ).

26. A significant increase in minor bleeding complications was observed among STEMI and elective PCI patients. In patients undergoing elective PCI, triple therapy had no beneficial effect - associated with an 80% increase in transfusions and an eightfold increase in thrombocytopenia.

27. Thromboxane A 2 receptor antagonists Thromboxane receptor α (TP α ) GPCR that is coupled to Gq and G12/13 Blocks TP activation through other ligands such as Endoperoxides Some have additional TXA2 synthase inhibition GPCRs – IP3/DAG – Ca ++

28. TERUTROBAN Oral reversible inhibitor of TP receptor Dose dependently prolonged occlusive thrombus formation in animal models Dose dependent inhibition of platelet aggregation in patients with peripheral artery disease RIDOGREL The drug is a combined TXA2 synthase inhibitor TXA2 receptor blocker Prostaglandin endoperoxide receptor antagonist While aspirin inhibits COX, ridogrel inhibitsTXA2 synthesis directly FAILED TO MEET PRIMARY ENDPOINT

29. PICOTAMIDE Combined inhibitor At variance with aspirin, does not interfere with endothelial PGI 2 production Moreover long-term picotamide treatment in diabetes promotes the reduction of microalbuminuria and the inhibition of growth of carotid plaques RAMATROBAN

30. Thrombin Receptor Antagonist

31. VORAPAXOR – approved on May 8, 2014 Oral Reversible antagonist PAR-1 – first agent High affinity and low molecular weight PAR-1 is a GPCR found in platelets and vascular endothelium – 40mg loading – 2.5mg maintenance Blocks the cellular activation of thrombin without inhibiting thrombin mediated cleavage of fibrinogen Does not influence hemostasis as well as bleeding time In theory this agent should result in less bleeding ATOPAXAR QT prolongation

32. vWF ANTAGONISTS AJW200 An IgG4 humanized monoclonal antibody to vWF which has been shown to specifically inhibit high-shear-stress-induced platelet aggregation. ARC1779 Continuous infusion increased platelet counts in critically ill TTP - preventing platelet aggregation and loss of platelets.

33. GPVI RECEPTOR ANTAGONISTS REVACEPT Dimeric Glycoprotein VI-Fc fusion protein Specifically and efficiently inhibited collagen-induced platelet aggregation   Under PHASE II trial

34. GPIb RECEPTOR ANTAGONISTS h6B4-Fab Is a murine monoclonal antibody , Targeting GPIb α and neutralizes the binding site of the vWF A1 domain

35. Aggregating the evidence on antiplatelet drugs: A review of recent clinical trials Author: Niteesh K. Choudhry , M.D., Ph.D., Nihar R. Desai, M.D., M.P.H. Consultants: Jerry Avorn , M.D., Michael Fischer, M.D., M.S.

36. THANK YOU