New Antithrombotic and Antiplatelet Drugs in CAD : (Factor Xa inhibitors, Direct Thrombin inhibitors and Prasugrel)

Limitations and Advantages of UFH and LMWH Biological limitations of UFH : 1. immune-mediated platelet activation Anti-Plt Factor4/Heparin complex -- heparin-induced thrombocytopenia (HIT) (2~15%) 2. effect on bone cells -- heparin-induced osteoporosis Pharmacokinetic limitations : variable anticoagulant response -- need for anticoagulant monitoring (AT-independent binding of UFH to plasma proteins) Major advantages of UFH over LMWH : 1. The anticoagulant effects of UFH : rapidly and completely neutralized by protamine 2. not cleared by the kidneys safer than LMWH in patients with renal insufficiency 3. Effective in contact activation pathway : block XI to Xia --- lesser thrombosis on catheter tips, stents, filter

Limitations and Advantages of LMWH UFH and LMWH More selective anti-xa activity upstream blockade of coagulation pathway Less non-specific tissue binding predictable anticoagulant effect fixed weight-determined dose long half life allowing once or twice daily administration Less platelet binding lower risk of heparin-induced thrombocytopaenia lower risk of osteopenia

INTRODUCTION : New anticoagulants

Indirect Factor Xa Inhibitors Arixtra (fondaparinux) Synthetic version of the pentasaccharide sequence of UFH and LMWH that binds to antithrombin and modifies its confirmation, inhibiting factor Xa. No monitoring indicated; only fondaparinux can be used to calibrate the anti- Xa assay Half life : 17hrs

OASIS-5: Comparison of Fondaparinux and Enoxaparin in Acute Coronary Syndromes - RESULTS - Yusuf S, et al. N Engl J Med 2006;354:1464-76

Current Indications and Usage for Arixtra Prophylaxis of DVT :hip fracture surgery, hip replacement surgery, knee replacement surgery, abdominal surgery who are at risk for thromboembolic complications Acute deep vein thrombosis when administered in conjunction with warfarin sodium Acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital

Direct (Non AT-Dependent) Xa Apixanban, Rivaroxaban Inhibitors Potent with high oral bioavailability : (Apixaban : 50~85%, Rivaroxaban 60~80%) Effective in preclinical models of venous and arterial thrombosis No organ toxicity in toxicology studies Elimination : Apixaban (~70% GI tract, ~25% renal), Ribaroxaban (~30% GI tract, ~65% renal) Half-life : Apixaban (~12 hrs), Ribaroxaban (~9hrs)

APPRAISE-1 trial (Circulation. 2009.6 ;119:2877-2885)

APPRAISE-1 trial Major Bleeding : -fall in hemoglobin of 2 g/dl -transfusion of 2 units of PRBC or whole blood -occurs in a critical location (intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial) Clinically Relevant Non-Major Bleeding : does not meet criteria for major bleeding, and that requires any medical or surgical intervention to treat the bleeding (Circulation. 2009.6 ;119:2877-2885)

Conclusion : Apixaban The addition of apixaban to contemporary antiplatelet therapy for 6 months f/u an acute coronary syndrome : -- dose dependent increase in bleeding -- trend toward a reduction in clinically important ischemic events The relative increase in bleeding and reduction in ischemic events appears similar among patients taking single (aspirin) or dual (aspirin plus clopidogrel) antiplatelet therapy Apixaban, at a total daily dose of between 5 and 10 mg, appears promising in patients with recent acute coronary syndromes receiving either aspirin or dual antiplatelet therapy and deserves further clinical investigation. (Circulation. 2009.6 ;119:2877-2885)

Direct Thrombin Inhibitors in CAD Parenteral drugs : Hirudin, Argatroban, Bivalirudin Oral drugs: Ximelagatran, Davigatran Advantage by mechanism : 1. Less non-specific protein binding 2. Direct action without a cofactor 3. Absence of known inhibitors 4. Less platelet binding More effective thrombin inhibition, Less platelet activation Less thrombocytopenia

Angiomax (bivalirudin) Synthetic molecule designed on the basis of structural studies of hirudin Undergoes reversible binding may lead to less bleeding. No antidote available for reversal. (Half life 25min) Therapeutic use FDA - approved Anticoagulation in patients undergoing PTCA in conjunction with aspirin Other Treatment of patients with HIT Anticoagulation for patients with HIT undergoing CABG Monitoring ACT for patients undergoing PTCA. ACT for patients undergoing CABG. aptt for patients with HIT or unstable angina.

Direct Thrombin Inhibitors HERO-2 (Death/Disabling Strok e/re-mi) % of patients 16 14 12 10 8 6 4 2 0 Heparin Bivalirudin 13.8% Odds Ratio 0.91 (0.83, 1.00) p=0.049 12.7% 0 5 10 15 20 25 30 White HD, et al. Lancet 2002

(Circulation. 2005 ;112:737)

ACUITY trial ACUITY Design. Stone GW et al. AHJ 2004;148:764 75

ACUITY trial N Engl J Med 2006;355:2203-16.

Antiplatelet agents:prasugrel Prasugrel : inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets.

Prasugrel Compared to Clopidogrel in Patients with Acute Coronary Syndromes Undergoing PCI with Stenting: the TRITON - TIMI 38 Stent Analysis

Prasugrel Compared to Clopidogrel in Patients with Acute Coronary Syndromes Undergoing PCI with Stenting: the TRITON - TIMI 38 Stent Analysis :RESULTS Wiviott SD, Braunwald E, McCabe CH et al NEJM2007

Prasugrel Compared to Clopidogrel in Patients with Acute Coronary Syndromes Undergoing PCI with Stenting: the TRITON - TIMI 38 Stent Analysis :RESULTS DES BMS

Prasugrel :Effient Indications : Acute coronary syndrome : reduce the rate of thrombotic cardiovascular events (including stent thrombosis) in PCI Dosage and Adminstration : single 60mg oral loading and continue 10mg orally once daily should also take aspirin may be adminstered with or without food Contraindications 1.Active bleeding (such as peptic ulcer, intracranial hemorrhage) other risk factor of bleeding : over 75yrs(except DM or history of MI patients), CABG or other surgical procedure (if possible, Effient should be discontinued at least 7days prior to CABG) 2. prior TIA or stroke (>3months) : higher risk thrombotic stroke (6.5 vs 4.2%), ICH (2.3% vs 1.2%) than clopidogrel