Hemostasis Overview. Overview of Normal Hemostasis Thrombophilias Hypercoagulable States. No Conflicts of Interest

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1 Overview of Normal Hemostasis Thrombophilias Hypercoagulable States Thomas W. Wakefield MD S. Martin Lindenauer Professor Section of Vascular Surgery University of Michigan No Conflicts of Interest Hemostasis Overview Primary: formation of soft platelet plug Begins with endothelial damage Vasoconstriction Platelet adhesion and aggregation Secondary Coagulation cascade leads to fibrin formation and cross-linking, strengthening the plug Fibrinolysis Inflammation Vandy and Wakefield 1

2 1% circulates in activated form The Vitamin-K Dependent Serine Proteases and Protein S Bind Ca 2+ on platelet surface Concentrations and Half-lives of the Coagulation Factors Factor Conc. (nmol/l) t1/2 (days) XI Thrombin IX 90 1 X VII V VIII Protein C Protein S Soft Platelet Plug Forms in 1-3 min Adhesion Gp Ib/IX/V Collagen vwf (bridge) Aggregation Gp IIb/IIIa Fibrinogen Activation 2

3 Platelet Activation Encourages Coagulation vwf: Two roles Adhesion (via collagen and glycoprotein Ib/IX/V) Protection of VIIIa Granule release Dense Ca 2+, ADP, TxA 2 These substances are vasoconstrictors, which increases shear, causing more aggregation Alpha Fibrinogen, vwf, factors V and VIII Shape change Pseudopodia P-Selectin Externalization of phosphatidyl serine (-) Acts as framework for binding Ca 2+ and vitamin K dependent factors Tissue Factor Hemostatic Envelope Fibroblasts Smooth muscle cells Leukocytes Vascular Injury Exposes subendothelial TF Upregulates TF production Plasma TF Relatively new concept Not quite freely, but as TM protein within microparticles of phospholipid membrane Increased in systemic inflammation Thrombin, Factor XIII, and Fibrin Thrombin stabilizes the platelet plug by splitting fibrinogen into fibrin Activates factor XIII, which cross links fibrin Soluble fibrin/fibrinogen converted to insoluble clot 3

4 Steps of the Cell-Based Model Initiation Small amounts of thrombin produced by subendothelial TF-bearing cells IXa is also produced Priming Small quantity of thrombin in synergy with exposed collagen binding Gp Ib/IX/V on platelets activation Propagation Complex formation on platelet surface Platelet Xase = IXa/VIII Platelet Prothrombinase = Xa/Va Overview of the Cell-Based Model Positive Feedback Endothelium-Derived Inhibitors Tissue Factor Pathway Inhibitor Circulating plasma proteinase inhibitor produced by endothelium Production increased by heparin Associated with lipoproteins, usually LDL Two mechanisms of coagulation inhibition TF/VIIa/Xa/TFPI complex, which prevents further TF/VIIa cleavage TFPI/Xa complex Thrombomodulin Expressed on the endothelial cell surface Forms complex with thrombin (IIa) IIa/TM catalyzes C APC (with Protein S as cofactor) APC deactivates factors Va and VIIIa But ONLY on endothelium, NOT on platelets! 4

5 Heparin Mediated Inhibitors Antithrombin Circulating plasma proteinase, member of Serpin family Inhibits the serine proteinases (IIa, Xa, IXa, XIa, TF/VIIa) By trapping thrombin, prevents Cleavage of fibrinopeptides A and B from fibrinogen Activation of V and VIII Activation of platelets Heparin accelerates its activity by up to 10,000x Heparin/antithrombin complex lives on endothelium Heparin cofactor II Also a member of the Serpin family Inhibits only thrombin (IIa) Heparin accelerates its activity by 1,000x Dermatan sulfate also accelerates its activity (produced by fibroblasts and SMCs) possibly more important as an extravascular thrombin inhibitor? An Overview of Fibrinolysis Major enzyme is plasmin Downregulated on platelets, upregulated on endothelium Complex interplay with coagulation cascade Tissue Plasminogen Activator (tpa) Blood levels typically low Released by endothelium in response to Thrombin Venous occlusion Endothelial injury 100X more efficient at activating plasmin when bound to fibrin Inhibited by PAI-1 5

6 Plasmin Acute phase reactant, synthesized by the liver Blood levels of plasminogen (inactive) are high In the presence of fibrin, activated by tpa Three roles: Cleaves fibrin/fibrinogen (major role) Cleaves other coagulation proteins Prevents adhesion of vwf to Gp Ib/IX/V Cleaves fibrin at Lys-Arg, leaving a stub which activates more plasmin (positive feedback) Lysine analoges distract plasmin Epsilon-aminocaproate and tranexamic acid When nothing else to eat, plasmin autocleaves itself Physiologically inhibited by alpha2-antiplasmin, but only when free from fibrin Fibrinolysis Inhibitors Plasminogen Activator Inhibitor (PAI-1) Blood levels increased after injury, allowing clot to persist Released by activated platelets Circulates at levels 7x higher than tpa Inhibited by APC, disinhibiting tpa Alpha2-antiplasmin Primary plasmin inhibitor Tethered to fibrin clot, where it inactivates plasmin Thrombin Activated Fibrinolysis Inhibitor (TAFI) Activated by IIa/TM Cleaves fibrin s C-terminal lysine, ending plasmin s positive feedback loop Inflammation: Cause or Effect? Endothelial cells are usually anti-inflammatory and antithrombotic NO, IL-10 (inhibits leukocyte adhesion) prostacyclin, TM, tpa Intimal injury endothelial activation inflammation Increased production of vwf, TF, PAI-1, and fv Increased surface expression of P- and E-Selectins Increased adhesion of leukocytes Systemic inflammation hypercoagulability Circulating endotoxin, IL-1, and TNF Increased TF expression Decreased TM expression Leukocytes express TF C4bBP, an Acute Phase Reactant binds Protein S in the blood 60% of Protein S is bound to C4bBP, and inactive Inflammation increases C4bBP, decreasing the % of free, active Protein S 20% of systemically ill patients have this acquired Protein S Deficiency 6

7 The Leukocyte as a Player in Hemostasis Hemostasis and Inflammation Selectins facilitate binding of leukocytes to endothelium, platelets, and each other In primate models, prophylactic inhibition of P-Selectin decreases VTE Activated platelets secrete chemoattractants Neutrophil activating peptide 2 (NAP-2) Platelet Factor 4 (PF4) Working model of DVT- timeline Initiation Resolution Fuchs et al.,

8 Hereditary Thrombophilic Disorders Activated Protein C Resistance Most frequently FV Leiden Prothrombin G20210A Protein C deficiency Protein S deficiency Antithrombin III deficiency MTHFR mutations, elevated homocysteine Elevated Factor VIII level Less Frequent Elevated Factor IX or XI Elevated Lp(a) Plasminogen deficiency Heparin Cofactor II deficiency Dysfibrinogenemia Plasminogen Activator Inhibitor Abnormality Venous Thrombosis Acquired Causes Age (1000x Difference, Very Young vs. Very Old) Malignancy (3-20% among those with VT, 6.2x) Surgery and Trauma (Up to 50-60% without Prophylaxis) Immobilization (Air flight, 1/10 or 1/10,000?) Oral Contraceptives (4-8x) Hormone Replacement Therapy (2-4x) Pregnancy (10x) and Puerperium (Greater) Antiphospholipid Antibodies (10x) Male Sex (Recurrent DVT, 3.6x)* Bauer et al, Hematology 2002(1):353; White et al, Thromb Haemost 90: , 2003 *Kyrle PA, et al, N Eng J Med 350: ,

9 Venous Thrombosis Genetic Causes Deficiencies of Natural Coagulation Inhibitors (Antithrombin, Protein C, S) 10x Factor V Leiden (up to 20% unselected, 50% selected VT) Heterozygous 3-8x, Homozygous 80x Prothrombin 20210A (up to 6% selected, 3x) Blood Group (non-o) 2-4x Methylene Tetrahydrofolate Reductase 677T (0.16x) Hyperhomocysteinemia (5-10% of population, 2x) High Levels of Clotting Factors (2-3x) Gene-Gene/Gene-Environment Interactions Bauer et al, Hematology (1):353, 2002 Risk of Recurrent Venous Thromboembolism (VTE) in Thrombophilia Compared to VTE Without a Thrombophilic Defect Thrombophilic Defect Rel. Risk Antithrombin, protein C, 2.5 or protein S deficiency Factor V Leiden mutation 1.4 Prothrombin 20210A mutation 1.4 Elevated Factor VIII:c 6 11 Mild hyperhomocysteinemia Antiphospholipid antibodies 2 9 Clinical Signs Indicative of Possible Thrombophilia Thrombosis at a young age (<40 yrs) Unprovoked thrombosis Recurrent thrombosis Thrombosis at an unusual site Mesentery, CNS venous sinus, portal vein Family history of thrombosis, particularly unprovoked, severe and in individuals <50 years of age 9

10 Antithrombin Deficiency Congenital: >100 known mutations, 0.1% of general population Homozygotes die in utero Acquired: cirrhosis, nephrotic syndrome, malnutrition, DIC Type I: decreased quantity and activity Type II: decreased activity only Antithrombin levels typically 40-70% of normal (140 mg/ml) 20x annual risk of VTE, 50-85% of these patients get VTE by 50 years old Accounts of 1% of VTE in unselected patients, but only 2% in young patients with family history or unusual location Antithrombin Deficiency Antithrombin levels are reduced by heparin therapy, acute thrombosis, liver disease, nephrotic syndrome, OCPs and pregnancy 60% of AT deficient patients will have recurrent thrombosis ATIII concentrates are available for replacement therapy during high risk situations such as surgery 10

11 Antithrombin Deficiency Diagnosis Inability to be Anticoagulated on Heparin Recurrent Thrombosis on Heparin Measure antigen and activity before warfarin or heparin are started (artificially increase/decrease levels) Tx: FFP and heparin Protein C Deficiency Autosomal dominant, 160 mutations known Purpura fulminans intrauterine death in homozygotes Type I: quantitative; Type II: qualitative Accounts for 3% of unselected patients with VTE and 50% will get a VTE by 50 years old Heterozygous protein C deficiency present in 1 in individuals in the general population Deficiency is present in 2-9% of individuals with venous thrombosis Levels of protein C in individuals heterozygously deficient may overlap with lower limits normal Acquired deficiencies of protein C are seen in disease states which affect vitamin K levels and liver function. Acute thrombosis lowers protein C levels. 11

12 Protein S Type Ia/b: quantitative; Type II: qualitative Accounts for 2% of patients with VTE 50% will get a VTE by 25 years old Vitamin K dependent protein that acts as cofactor for protein C in inactivating FVa and FVIIIa 40% Protein S circulates in a free active form, the remainder is bound to C4B binding protein Protein S levels increase with age and females have lower levels than males. Protein S levels are reduced in liver disease, nephrotic syndrome, inflammation, acute thrombosis, by OCP use and in pregnancy and breastfeeding Protein C/S Deficiency Diagnosis Functional/Antigenic Level Protein C Antigenic Level Protein S (Free) C4b Binding Protein will Decrease Free Protein Esmon, Science 1987 Factor V Leiden Factor V Leiden accounts for 90% of activated protein C resistance Factor V Leiden mutation is Arg506Gln located near the activated protein C cleavage site on activated factor V, conferring resistance to inactivation Prevalence 10% of Caucasians and 1.5 % African Americans. Not present in Native Africans, Chinese, Japanese, or Native Americans Heterozygous mutation increases risk of thrombosis 5-7x 12

13 Activated Protein C Resistance 95% of cases are V Leiden (506 Glu Arg) APC cannot be deactivated by IIa/TM Homozygous mutation confers 80x risk of thrombosis Heterozygous mutation only 7x risk of thrombosis not all heterozygotes require lifetime anticoagulation 5% of general population are heterozygous for V Leiden Accounts for 20-60% of all VTE <30% of heterozygotes will get VTE by 50 years old, but only 60% of homozygotes Venous > arterial thrombosis Factor V Leiden Diagnosis Functional, Genetic Assay Treatment Anticoagulation if History of Thrombosis Prothrombin G20210A Second most frequent cause for hypercoagulability in Caucasians Prevalence 1-2% of Caucasians Mutation occurs in the 3 untranslated region of the prothrombin gene Results in increased levels of prothrombin (>1.15 units/ml) Independently confers a 2.8 fold increase in thrombosis risk 13

14 Patients Heterozygous for these mutations Factor V Leiden (No Increased Risk for Recurrent DVT) Prothrombin 20210A (No Increased Risk for Recurrent DVT) Both Factor V Leiden & Prothrombin 20210A Relative Risk for Recurrent DVT 2.6x (if first event spontaneous) Spontaneous Recurrences 3.7x If first event Spontaneous 5.4x vs Factor V Leiden Alone De Stefano et al, NEJM 341: , 1999 Combined Deficiencies 162 DVT, 336 Controls Independent Risk Factors for Thrombosis Het, Hom Factor V Leiden (16.3-fold) Het, Hom Prothrombin (3.6-fold) Hom Methylenetetrahydrofolate (hyperhomocystine) (MTHFR, 2.1-fold) 2 or more % vs 0.9% Factor V Leiden + Prothrombin (58.6-fold) Factor V Leiden + MTHFR (35-fold) Prothrombin MTHFR (7.7-fold) Salomon et al, Arterioscler Thromb Vasc Biol 19: , 1999 Hyperhomocysteinemia Mild-moderate hyperhomocysteinemia (>15mmol/L) associated with premature atherosclerosis Hyperhomocysteinemia exerts oxidative damage to the endothelium Accounts for 10% of the population risk for CAD 9 Case-Control Studies VTE: 2.95x ( ) but if <60 yoa; VTE: 4.37 ( ) Ray, Arch Intern Med 158:2101,

15 Hyperhomocystinemia Diagnosis Homocystine Levels Treatment Vitamin B6, B12, Folate? Antiphospholipid Syndrome Clinical criteria ( 1 must be present): 1. Vascular thrombosis: 1 clinical episode of, objectively confirmed, arterial, venous, or small vessel thrombosis 2. Pregnancy morbidity: 1 unexplained fetal 10 weeks EGA 1 premature birth ( 34th week of gestation) due to eclampsia, severe pre-eclampsia, or placental insufficiency 3 unexplained consecutive spontaneous <10 weeks EGA Revised Sapporo/Sydney Criteria. JTH 2006;4: Antiphospholipid Syndrome Laboratory criteria ( 1 must be present): LA (+) 2 occasions, at least 12 weeks apart, according to ISTH guidelines: prolonged PL-based clotting assay, lack of correction with 1:1 mix, and correction with excess PL ACLA and/or anti-β2 glycoprotein-i antibody: medium or high IgG and/or IgM isotype titer 2 occasions, at least 12 weeks apart Standardized ELISA assays Revised Sapporo/Sydney Criteria. JTH 2006;4:

16 Lupus Anticoagulant/Antiphospholipid Syndrome Actives thrombin, inhibits Protein C Treatment Anticoagulation in the Face of Thrombosis INR >3.0 Now INR Treat for 3-6 months, then Retest (especially if Intermediate Titer) Khamashta et al, NEJM 1995 Factor VIII Elevated Factor VIII and DVT Dose-response Relationship >150IU/dl, 4.8x Odds Ratio Koster et al, Lancet 345: , 1995 Elevated Factor VIII and Recurrent DVT >234IU/dl (90 Percentile), 11.4x Odds Ratio 6.7x after Adjusting for Age, Sex, Factor V Leiden, Prothrombin G20210A, Duration of Coumadin Kyrle et al, NEJM 343: , 2000 Heparin-Induced Thrombocytopenia Absolute Risk 0.2% LMWH 2.6% Standard Unfractionated Heparin Harm Associated with UFH more Frequent than with LMWH VTE associated with HIT <1% LMWH, approx 12-13% with UFH (OR 21x) with Higher Risk for Mortality Levine RL et al, Chest 130: , 2006 Hull R et al (personal communication) 16

17 HIT Platelet range Typically 40-80,000, but may be higher if high starting point 50% drop from pre-heparin exposure values <25,000 should raise suspicion of another dx Typically occurs after 4 days of treatment Earlier: if prior heparin exposure within 100 days may occur < 24 hours after re-exposure Later: may occur 4-6 weeks after heparin is stopped LE DVT (or UE if catheter in place), skin or adrenal gland necrosis May cause arterial thrombi, causing cold foot, stroke, MI, mesenteric infarcts, and renal artery thrombosis MECHANISMS OF HEPARIN- INDUCED THROMBOCYTOPENIA Heparin in the presence of PF4 form a complex that rears an Ab (IgG, IgA, IgM) that binds to platelet FcgRIIa receptors leading to their activation with the release of procoagulant microparticles. Diagnosis and Treatment of HIT Diagnosis ELISA: tests for PF4/heparin complex Ig s But these are present in 10% of patients treated with heparin SRA: release of alpha granules However, this is a clinical diagnosis Treatment Stop heparin Observe for thrombosis Argatroban or lepirudin Plan to anticoagulate for days Future use of heparin after Ig s disappear is controversial 17

18 Hirudins Direct thrombin inhibitors not requiring AT activity Lepirudin (Refludan) is 65AA protein that is the most potent thrombin inhibitor. Non-reversible, can be difficult to monitor, renal excretion Bivalrudin (angiomax) is shorter acting requiring a drip Lepirudin 82 patients Platelet Counts Rose (89%) Death, Amputation, New Thromboembolic Complications Significantly Reduced (p=0.014) Adjusted Hazard Ratio compared to Historical Controls 0.28 (p=0.003) Bleeding Rates Similar Greienacher A et al, Circulation 99:73-80, Argatroban Synthetic thrombin inhibitor Little or no effect on factor Xa Liver metabolism Fairly predictable PTT nomogram starting with infusion of 2-4mcg/kg/hr with max of 10mcg/kg/hr 18

19 Need to overlap with coumadin therapy until INR is >4 due to false elevation of INR with argatroban. Argatroban Synthetic pentasaccharide that is identical to the AT binding sequence from heparin Potentiates ATIII to rapidly inhibit factor Xa Can be used in HIT pts Fondaparinux (Pentasaccharide) Prophylaxis : Major Orthopedic Surgery (n7344) 2.5mg, 6 hrs s/p OR vs. Enoxaparin hrs after OR Risk Reduction 55% Major Bleeding Increased but Critical Bleeding Not Different Turpie AG et al, Arch Intern Med 162: , 2002 Prophylaxis : General Medical (n849 > 65yoa) Total VTE: 10.5% down to 5.6% (p<0.05) Cohen AT et al, J Thromb Haemost 2003; 1(suppl):P2046 Wolozinsky M et al, Am J Cardiovasc Drug 5: , 2005 Prophylaxis : Abdominal Surgery (n2048) Total DVT: 6.1% down to 4.6% Major Bleeding 3.4% vs. 2.4% Agnelli G et al, Brit J Surg 92: , 2005 Extended Prophylaxis : Hip Fracture (n656) Total DVT: 35% down to 1.4% (p<0.001) Symptomatic DVT: 2.7% down to 0.3% (p<0.05) Eriksson et Lassen, PENTHIFRA-Plus, Arch Intern Med 163: ,

20 Fondaparinux (Pentasaccharide) Treatment : 7.5mg (*5-10 based on wt) SubQ qd (at least 5 days), 3 Mo FU Matisse Investigators DVT 154 Centers, 23 Countries, 2205 Patients, >30% OP PE 214 Centers, 20 Countries, 2213 Patients, 15% OP DVT Recurrence/Major Bleeding 3.9%/1.1% Fondaparinux 4.1%/1.2% Enoxaparin 1mg/kg bid *PE Recurrence/Major Bleeding 3.8%/1.3% Fondaparinux 5%/1.1% UFH Dose-Adjusted Mortality Equal in Each Study Buller HR et al, Ann Intern Med 140: , 2004 *Buller HR et al, N Eng J Med 349: , 2003 ARIXTRA (Fondaparinux sodium) Injection is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism: in patients undergoing abdominal surgery; in patients undergoing hip fracture surgery; including extended prophylaxis; in patients undergoing hip replacement surgery; in patients undergoing knee replacement surgery; the treatment of acute deep vein thrombosis when administered in conjunction with warfarin sodium; the treatment of acute pulmonary embolism when administered in conjunction with warfarin sodium when initial therapy is administered in the hospital. 2.5mg SubQ daily 20

21 VKA LMWH Heparin Rivaroxaban Apixaban Dabigatran Edoxaban Route PO SQ IV/SQ PO PO PO PO Frequency QD BID or QD Infusion BID/TID QD BID QD/BID QD/BID VTE Prophylaxis data Yes Yes Yes Yes Yes Yes On going VTE Treatment Data Yes Yes Yes On going On going Yes On going Partially Protamine Reversibility FFP with / short No/unknow No/unknown Novoseven No/unknown n protamine half-life none none none none Food Interactions Many No No apparent apparent apparent apparent Cost cheap expensive cheap unknown unknown unknown unknown Commercially available Yes Yes Yes Some countries Knepper and Wakefield, NW Symposium, 2010 No Some countries No VTE Prophylaxis, VTE Treatment, Atrial Fibrillation Treatment, ACS, Medical Patients Rivaroxaban: An Oral Direct Xa Inhibitor Direct, specific, competitive Factor Xa inhibitor (Bayer) Inhibits free and fibrin-bound Factor Xa activity and prothrombinase activity Potent anticoagulant effects Does not directly inhibit thrombin, but inhibits thrombin generation via direct inhibition of Factor Xa activity Rapid onset 2-4 hrs; Half-life 5-9 hrs, but effect up to 24 hrs High oral bioavailability > 80% Does not affect agonist-induced platelet aggregation, and therefore has no direct effect on primary hemostasis Does not require a cofactor such as antithrombin May be safely administered with concomitant agents including aspirin, enoxaparin, digoxin, naproxen, ranitidine, antacids No dosage adjustment for gender, age, extreme body weight Perzborn et al., J Thromb Haemost 2005; ICT 2004; Depasse et al., ISTH 2005 Kubitza et al., J Clin Pharmacol 200; Eriksson et al. Circulation 2006;114; ; Fareed et al., ISTH

22 RECORD Phase III Trials: VTE Prevention (>10,000 patients worldwide) Hip Trials Trial Design DB, R, C Non-inferiority Study Extended prevention of VTE in elective total hip replacement patients Dosing Rivaroxaban: 10mg; once-daily; 35 days Enoxaparin: 40mg; once-daily; 35 days Knee Trials DB, R, C Rivaroxaban: Parallel Arm, Double Dummy, 10mg; once-daily; 35 days Risk Superiority Reduction Study 31% Enoxaparin: - 79% Extended prevention of VTE elective 40mg; once-daily; 14 days Superiority: Record 1, 2; Non-Inferiority: Record 3, 4 total hip replacement patients DB, R, C Rivaroxaban: Prevention of VTE in elective total 10mg; once-daily; 14 days knee replacement patients Enoxaparin: 40mg; once-daily; 14 days DB, R, C Prevention of VTE in elective total knee replacement patients Rivaroxaban: 10mg; once-daily; 14 days Enoxaparin: 30mg bid; 14 days Rivaroxaban (Einstein-DVT) Rivaroxaban compared with standard therapy in an open-label noninferiority study involving more than 3,400 patients with acute symptomatic deep vein thrombosis (DVT) 15 mg twice-daily for the first three weeks, followed by oral Rivaroxaban 20 mg once-daily vs. Standard therapy Positive Results - non-inferiority in the primary endpoint symptomatic recurrent DVT and non-fatal or fatal PE (2.1% vs. 3.0%) without any increase in Bleeding In parallel, double-blind, randomized event-driven superiority study that compared Rivaroxaban 20 mg once-daily vs. Placebo for an additional 6-12 months in those who had completed 6-12 months of Treatment (approx 1200 patients) Rivaroxaban showed Superiority (1.3% events vs 7.1%) with Increased Bleeding (0.7% vs. 0%) N Eng J Med 363: , 2010 Rivaroxaban (Einstein-PE) Rivaroxaban compared with standard therapy in an open-label noninferiority study involving 4832 patients with acute symptomatic pulmonary embolism (PE) with or without DVT Primary Efficacy Outcome was Symptomatic Recurrent VTE 15 mg twice-daily for the first three weeks, followed by oral Rivaroxaban 20 mg once-daily vs. Standard therapy Positive Results - non-inferiority in the primary endpoint symptomatic recurrent DVT and non-fatal or fatal PE (2.1% vs. 1.8%) without any increase in Bleeding or other Adverse Effects N Eng J Med 366: ,

23 Rivaroxaban (Rocket AF) Double-Blind Trial 14,264 Patients with Nonvalvular AF + 2 additional risk factors or history of prior stroke, TIAs, or systemic embolization Rivaroxaban, 20mg daily vs. Dose-adjusted Warfarin Primary End point Stroke or Systemic Embolism Primary Analysis: 1.7%/year vs. 2.2%/year (HR 0.79, p<0.001 for Noninferiority) Intention to Treat: 2.1%/year vs. 2.4%/year (HR 0.88, p<0.001 for Noninferiority) Major and Nonmajor Bleeding: 14.9%/year vs. 14.5%/year, NS Intracranial Hemorrhage: 0.5% vs. 0.7%, p=0.02 Fatal Bleeding: 0.2% vs. 0.5%, p=0.003 In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant betweengroup difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. Patel MR et al, N Engl J Med 365: , 2011 Rivaroxaban (ATLAS ACS 2-TIMI 51) Double-Blind, Placebo-controlled Trial 15,526 Patients with Recent ACS Rivaroxaban, 2.5 or 5mg daily vs. Placebo Mean 13 mo and up to 31 mo Primary Efficacy End point Death from CV causes, MI, Stroke Primary Efficacy End point 8.9% vs. 10.7% (HR 0.84, p=0.008) Both twice-daily 2.5mg dose and 5.0mg dose Death (CV cause) 2.7% vs. 4.1%, p=0.002 Death (any cause) 2.9% vs. 4.5%, p= mg dose, not 5mg dose Major Bleeding: 2.1% vs. 0.6%, p<0.001 Intracranial Hemorrhage: 0.6% vs. 0.2%, p=0.009 Fatal Bleeding: 0.3% vs. 0.2%, NS Fatal Bleeding: 2.5mg 0.1% vs. 5mg 0.4%, p=0.04 Mega JL et al, N Engl J Med 2011 Nov 13. [Epub ahead of print] Rivaroxaban (MAGELLAN) Rivaroxaban compared to Enoxaparin for Thrombosis Prophylaxis in High-risk Medical Patients 10mg Rivaroxaban daily vs. Enoxaparin 40mg daily At Day 10, Rates of Thrombosis 2.7% vs. 2.7% At Day 10, Bleeding 2.8% vs. 1.2% Full Study Data Pending Cohen AT et al, J Thromb Thrombolysis 31: , 2011 Soff GA, ATVB 32: ,

24 Rivaroxaban (Xarelto R ) Status Approved in Canada and Europe for prophylaxis after TKR and THR Under review by FDA for Orthopedic surgery Ongoing phase 3 studies in VTE and ACS Approved by FDA for VTE Prophylaxis for Hip (35 days) or Knee (12 days) Replacement, and for Stroke and Embolization Prevention in Nonvalvular Atrial Fibrillation FDA has given Priority Status for review of treatment indication for DVT, PE, and to prevent Recurrence of both (July 2012) Apixaban: An Oral Direct Factor Xa Inhibitor Direct, reversible factor Xa inhibitor (Bristol-Myers Squibb) Rapid onset, peak within 3 hours Bioavailability of 34%-88%, Distribution in Blood Long half life, slightly longer in elderly (15 hours) Multiple elimination pathways 25% renal 75% biliary Follow-up to Razaxaban (halted due to high bleeding) Perzborn et al., J Thromb Haemost 2005 Kubitza et al., J Clin Pharmacol 2007 Apixaban ADVANCE-1, Apixaban 2.5mg twice-daily had clinically comparable efficacy with twice-daily 30 mg Enoxaparin both starting after TKR (did not meet Noninferiority target); drugs for days 1599 Apixaban, 1596 Enoxaparin (VTE in 9.0% vs. 8.8%) With significantly less major or clinically relevant non-major bleeding 2.9% vs. 4.3% (p=0.03) Lassen MR et al, N Engl J Med 361: , 2009 However, did meet Noninferiority Target in ADVANCE-2, a study of Apixaban 2.5mg twice daily compared to Enoxaparin 40mg once daily for TKR 1528 Apixaban begun h after closure, 1529 Enoxaparin 12 h before surgery 1973 eligible for primary efficacy analysis, drugs for days The primary outcome 147/976 apixaban patients (15.1%) and 243/997 enoxaparin patients (24.4%) (RR 0.62, p<0.0001) Major or clinically relevant non-major bleeding occurred in 53/1501 apixaban patients (3.5%) and 72/1508 enoxaparin patients (4.8%) p= Lassen MR et al, Lancet 375: ,

25 Apixaban (ADVANCE-3) Thromboprophylaxis for Hip replacement Double-Blind, Double-Dummy 5407 patients randomized 2.5mg bid (begun hrs after wound closure) vs. Enoxaparin 40mg qd (initiated 12 hrs before surgery) Prophylaxis continued for 35 days; FU past 60 days Primary Efficacy was Composite of Asymptomatic or Symptomatic DVT, Nonfatal PE, or Death from any Cause Apixaban 1.4% vs. Enoxaparain 3.9% (RR 0.36, P<0.001 for Noninferiority and Superiority) Major and Clinically Relevant Nonmajor Bleeding Apixaban 4.8% vs. Enoxaparin 5.0% Lassen MR et al, N Engl J Med 363: , 2010 Apixaban (Botticelli Dose-ranging study) Symptomatic DVT Apixaban 5mg Twice Daily for 3 months Apixaban 10mg Twice Daily for 3 months Apixaban 20mg Once Daily for 3 months LMWH followed by Warfarin for 3 months Primary Efficacy End Point (3 months) Composite Symptomatic Recurrent VTE and Clincal Deterioration Safety End Point Major and Clinically Relevant Non-major Bleeding No Significant Differences between Doses No Apixaban Dose-Response Relationship 4.7% Apixaban, 4.2% LMWH VTE 7.3% Apixaban, 7.9% LMWH Bleeding Buller H et al, J Thromb Haemost 6: , 2008 Apixaban (Eliquis R ) Status Under review by FDA for Orthopedic surgery Ongoing phase 3 studies in AF, VTE treatment, VTE prevention, and ACS FDA has twice delayed decision, asking for more trial data June 2012 AVERROES study was stopped for Atrial Fibrillation and Stroke Prevention Aug 31, 2010, Apixaban vs. Aspirin for AF at Risk for Stroke However, its use was halted by FDA for ACS on Nov 18, 2010 The plug was pulled on a study of 10,800 patients with acute coronary syndrome after an independent data monitoring committee found a "clinically important increase in bleeding" that was not offset by the benefits of the drug. Alexander J et al, N Eng J Med 365: ,

26 Apixaban (APPRAISE-2) 5mg twice-daily apixaban to standard anti-platelet therapy following acute coronary syndrome. The primary outcome was a composite of cardiovascular death, myocardial infarction and ischemic stroke 7.5% apixaban vs. 7.9% placebo, NS (p=0.51). Major bleeding: 1.3% apixaban vs. 0.5% placebo (p=0.001). Addition of apixaban did not decrease the composite outcome while having a significant increase in major bleeding risk. Alexander J et al, N Eng J Med 365: , 2011 Apixaban Status Apixaban (ADOPT) Thromboprophylaxis for Medically Ill Patient Double-Blind, Double-Dummy, Placebo-Controlled Acutely Ill Patients with CHF, Respiratory Failure, and at least one Additional Risk Factor for VTE, Hospitalized, with expected stay of at least 3d 4495 patients randomized (n2211, n2284) 2.5mg bid for 30d vs. Enoxaparin 40mg qd for 6-14d Primary Efficacy was 30d Composite of Death (from VTE), PE, Symptomatic DVT, or Asymptomatic Proximal-leg DVT by Compression US Apixaban 2.71% vs. Enoxaparain 3.06% (RR 0.87, P=0.44) Major Bleeding Apixaban 0.47% vs. Enoxaparin 0.19% (RR 2.58, p=0.04) Goldhaber et al, N Engl J Med 365: ,

27 Dabigatran Etexilate Dabigatran etexilate is a new oral direct thrombin inhibitor: 1-3 (Boehringer Ingelheim) Predictable anticoagulant effect Fixed dose No need for monitoring Oral Bioavailability 6%, Half-life hrs Renal Excretion, Possible Reversal with afvii (Novoseven R ) Increased Bleeding with Escalating Doses (Bistro II) Dabigatran Binds directly to thrombin with a high affinity and specificity 4-5 Amiodarone increases bioavailability, Pantoprazole decreases bioavailability 1. Eriksson BI et al. J Thromb Haemost 2: , Eriksson BI et al; for BISTRO II Study Group J Thromb Haemost.3: , Wallentin L et al; PETRO Investigators. Eur Heart J 26(Suppl):482, Stassen JM et al. 28th Congress of the International Society on Thrombosis and Haemostasis; July 6-12, 2001; Paris, France. 5. Hauel NH et al. J Med Chem 45: , 2002 RE-NOVATE: Dabigatran etexilate in total hip replacement (Phase III) Start evening before surgery Enoxaparin 40 mg qd N=3494 R Start 1-4 hours postoperatively Dabigatran etexilate 75/150 mg qd 110/220 mg qd Randomization Venography Day Follow-up weeks Dabigatran etexilate and enoxaparin were given for days after surgery Central adjudication of all efficacy and safety outcomes Eriksson BI et al; for RE-NOVATE Study Group. Lancet 370: RE-NOVATE Major VTE or VTE-related mortality N=3494 Total hip replacement Patients (%) Dabigatran etexilate 40 mg OD VTE=venous thromboembolism 27

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