Dr.RENJU.S.RAVI MD

NEWER ANTI-PLATELETS

• 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

Hemostasis and thrombosis primarily involve the interplay among three factors

• Vessel wall • Coagulation proteins • Platelets

PRIMARY HEMOSTASIS

SECONDARY HEMOSTASIS

PLATELET PATHOPHYSIOLOGY

• platelets produced per day

• Anucleate cells

• Source of chemokines, cytokines that are preformed and stored as granules

• Activated platelets synthesize TXA2

Pathophysiology of the Thrombus

ANTI-THROMBOTIC DRUGS

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

ANTI-PLATELET DRUGS

• Aspirin COX-1 inhibitor :

• Ticlopidine , Clopidogrel , Prasugrel

P2Y12 inhibitors :

• Abciximab , Tirofiban , Eptifibatide

GPIIB/IIIA inhibitors :

• DipyridamolePhosphodiesterase inhibitors :

Bleedingrisk

Thromboticrisk

Will any drug ever prevent thrombosis without causing bleeding ?

NEWER ANTI-PLATELET AGENTS

• Ticagrelor, Elinogrel, Cangrelor, BX 667

P2Y12 inhibitors:

• RevaceptGPVI

receptor antagonis

ts: • Terutroban, Picotamide,

Ridogrel, EV-077, Z-335, BM-573

TXA2 receptor

antagonists:

• Vorapaxar, Atopaxar, SCH 205831, SCH 602539

Thrombin receptor

antagonists:

• Z4A5GPIIb/IIIa antagonist:

• AJW200, ARC1779, ARC15105, ALX-0081, 82D6 A3

vWF antagonists

:

GPIb receptor antagonists: h6B4-Fab, GPG-290, SZ2

Serotonin receptor inhibitor: APD791

Prostaglandin E3 receptor antagonist: DG-041

Nitric oxide donors: LA846, LA419

Phosphatidylinositol 3 kinase inhibitor: TGX-221

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

PHOSPHODIESTERASE ANTAGONISTS

CILOSTAZOLE

P2Y12 INHIBITORS

• ADP receptors

• P2Y1 and P2Y12 subtypes

• GPCR

• Both needed for aggregation – P2Y12 pathway plays a principal role

ADP RECEPTOR ANTAGONIS

T

Vasodilator stimulatedphosphoprotein

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

• 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

CANGRELOR

• Rapid onset and offset of action – iv route

• Ultra-short half life 3-6 minutes

• Infusion of 4μg/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

• 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

GPIIa/IIIb INHIBITORS• It’s a platelet surface integrin

• Designated as αIIbβ3

• Main use: • Percutaneous Intervention (PCI) • Limited efficacy after Myocardial

Infarction

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

HgeThrombocytopeniaExpensive

HgeThrombocytopenia

HgeThrombocytopenia

• 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)

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

• OTHER ORAL GPIIa/IIIb INHIBITORS

• Orbofiban – PHASE III• Lotrafiban – PHASE III• Sibrafiban

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).

• 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.

THROMBOXANE A2 RECEPTOR ANTAGONISTS

• Thromboxane receptorα (TPα)• 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++

• 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

PICOTAMIDE• Combined inhibitor • At variance with aspirin, does not

interfere with endothelial PGI2 production

• Moreover long-term picotamide treatment in diabetes promotes the reduction of microalbuminuria and the inhibition of growth of carotid plaques

RAMATROBAN

Thrombin Receptor Antagonist

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

vWF ANTAGONISTSAJW200

• 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.

GPVI RECEPTOR ANTAGONISTS

REVACEPT

• Dimeric Glycoprotein VI-Fc fusion protein

• Specifically and efficiently inhibited collagen-induced platelet aggregation 

• Under PHASE II trial

GPIb RECEPTOR ANTAGONISTS

h6B4-Fab• Is a murine monoclonal antibody,

• Targeting GPIbα and neutralizes the binding site of the vWF A1 domain

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.

THANK YOU