Anticoagulation: Current and Future therapies

1. Muhammad K. Ali, MDEmory University School of Medicine Anticoagulation: Current and Future therapies

2. History • Heparin • Discovered in 1916 by Jay Maclean (MS-2 Johns Hopkins) • Heparin (from greek hepar or liver) • Medically safe heparin first produced at Karolinska Instituet and then Connaught Labs affiliated with University of Toronto • First human trials in 1937

3. Mechanism of action • Heparin binds to the enzyme inhibitor antithrombin III (AT) • Conformational change that results in its activation through an increase in the flexibility of its reactive site loop • Activated AT then inactivates thrombin and other proteases involved in blood clotting, most notably factor Xa • Rate of inactivation of these proteases by AT can increase by up to 1000-fold due to heparin binding • Antidote: Protamine

4. Limitations • Narrow therapeutic window of adequate anticoagulation without bleeding • Highly variable dose-response relation requiring laboratory monitoring • Reduced ability to; • Inactivate thrombin bound to fibrin • Factor Xa bound to activated platelets within a thrombus • Thrombus may continue to grow during heparin therapy or clotting may be reactivated after heparin has been discontinued • Heparin induced thrombocytopenia

5. Pathophysiology of HIT • Administration of heparin/ other sulfated oligosaccharides for 4 + days can trigger an antibody response • IgG, IgM, and IgA antibodies are provoked by the highly immunogenic complex of heparin and platelet factor 4 (PF4) • PF4 is a heparin-neutralizing protein contained in the alpha granules of platelets, released from the platelet upon its activation

6. Naturally-occurring anti-PF4/heparin antibodies are present in 3 to 8 % of the normal population • Preimmunization by antigens mimicking PF4/heparin complexes • PF4 complexes with negatively-charged polysaccharides on the surface of bacteria (present in patients with periodontal disease) • May be responsible for the rapid appearance of these antibodies following treatment with heparin

7. Heparin-PF4 complex • Binds to an activated platelet surface and is recognized by the Fab region of the HIT antibody • Forming a heparin-PF4-antibody complex on the platelet surface • Fc portion of this bound IgG • Activates the same or adjacent platelets through the Fc gamma RIIA receptors on the platelet surfac • Additional platelet activation with further release of PF4, creating a positive feedback loop

8. Activated platelets with the heparin-PF4-antibody complex attached to their surface • Undergo aggregation and are removed prematurely from the circulation leading to thrombocytopenia (HIT) • Generation of procoagulant platelet-derived microparticles, frequently resulting in thrombin generation and thrombosis (HITT)

9. Antibody complex may also activate microvascular endothelial cells, resulting in augmented release of Interleukin-6, von Willebrand factor, and other adhesion molecules • Not clear whether these antibodies can be associated with thrombosis in the absence of relative or absolute thrombocytopenia

11. Warfarin • Derived from Dicoumarol which is a coumarinderivative found naturally in spoiled sweet clover in 1920s • Initially introduced as a pesticide in 1948 • Approved as a medication in 1954 • Most widely prescribed anticoagulant in North America • Warfarin name is an acronym • Warf- WISCONSIN ALUMNI RESEARCH FOUNDATION • Arin- from coumarin

12. Mechanism of action • Inhibits the vitamin K-dependent synthesis of biologically active forms of: • Calcium-dependent clotting factors II, VII, IX & X, • Regulatory factors protein C, S, & Z • May also affect other proteins • Osteocalcin • Matrix Gla protein • Antidote: Vitamin K

13. Limitations • A therapeutic INR has to be properly maintained and monitored frequently • Therapeutic level is affected by many factors including diet, medication genetics and illness • Narrow therapeutic range may cause under anticoagulation (causing thrombus formation) or over anticoagulation (leading to hemorrhage) • Constant monitoring is inconvenient for patients and costly • The action of the drug takes 72-96 hours to become effective & a rapidly acting parenteralanticoagulatant (heparin) has to be administered until a therapeutic INR is achieved • Many drugs increases or decreases the anticoagulant effect of warfarin , resulting in bleeding or thrombosis • Leading drug responsible for emergency hospital visits among the elderly

14. Endothelial function

15. Classic coagulation pthways

16. Newer Model

17. Role of Thrombin •  Final enzyme of the clotting cascade • Structure (X-ray crystallography) • Deep groove on one side of the molecule • Active site of the enzyme is buried deep within this groove • Access is protected by the surrounding structures, some of which protrude into the opening and shield the active site • Residues important in thrombin-activatable fibrinolysis inhibitor (TAFI) activation are located above the active site cleft • Residues involved in protein C activation are located below the active site cleft • Two additional important positively charged patches at opposite poles • Exosite I • Interacts with many of its physiologically relevant substrates, such as the thrombin receptor, fibrinogen, factor V, protein C, and thrombomodulin • Exosite II • Interacts with heparin and endogenous heparan sulfate

18. Rationale for newer agents • Cost • Logisitics • Monitoring • Limitations/ Complications • Oral vs Parenteral • Efficacy • Safety

19. Direct Thrombin Inhibitors • Recombinant Hirudin (Lepirudin, bivalirudin, desirudin) • 65-amino-acid protein • Originally extracted from the salivary gland of the medicinal leech (Hirudomedicinalis) • Binds to thrombin • Via direct interaction with the active site • Carboxyl tail of hirudin also binds to the exosite I, giving rise to very high binding affinity • Nonbinding to PF4 clinically important since antibodies responsible for HIT are provoked by the complex of heparin and platelet factor 4 (PF4) on the platelet surface

20. Hirudin analogues • Anticoagulant activity monitored by the aPTT • Approved for the Rx of heparin-induced thrombocytopenia (HIT) • Bivalirudin • FDA approved for unstable angina in patients undergoing PCI • May benefit patients with STEMI • Cost and lack of an effective antidote • Primarily renal clearance, caution in CKD • Anaphylactoid reactions • Patients previously treated with hirudin or its analogs, including desirudin itself, should not receive desirudin

21. Argatroban (Acova) • Smaller molecule C/W Hirudin • Only interacts with the active site of thrombin • Short in vivo plasma half-life • Monitored by the aPTT • Dose-dependent changes seen in the PT/ INR • Dosing adjustment with hepatic dysfunction only • FDA: Prophylaxis or Rx of thrombosis in HIT • Adjunct to thrombolysis in AMI (not FDA approved)

22. Dabigatran (Pradaxa) • Orally active direct thrombin inhibitor • Prodrug is converted to the active compound by non-specific esterases, binds directly to thrombin with high affinity and specificity • Indication • Prevention of VTE after TK or TH arthroplasty • Treatment of acute VTE • Prevention of stroke in atrial fibrillation

23. Pharmacokinetics • ½ life approx 12 to 14 hours (normal renal function , twice daily dosing) • Primarily renal excretion (unchanged drug) • Prolonged in elderly and with renal dysfunction • C/I if CrCl < 15 ml/ min or HD dependent • Dose adjustment if Cr Cl < 30 ml/min, also > 75 , 80 y/o age • Need to check baseline renal function and then annually in > 75 y/o age and GFR < 50 ml/ min

24. Drug stability/ Monitoring • Capsules should only be dispensed and stored in the original bottle (with desiccant) or blister package • Pills must be used within four months once the bottle is opened • Should not be crushed or opened before being administered (not for feeding tubes) • Predictable Pharmacokinetcs • Routine monitoring for coagulation not recommended

25. Drug interactions • Substrate for the efflux transporter P-glycoprotein • Contraindicated, avoid co-admininstration or dose modification with several drugs • Rifampin • Quinidine • Ketoconazole, • Verapamil • Amiodarone • Clarithromycin

27. Reversal strategies • No antidote available • Reversal of anticoagulant effect • Drug discontinuation (short ½ life) in normal renal function • Can be dialyzed in patients with renal impairment • Charcoal hemofiltration/ Enhanced diuresis • Other drugs that may potentiate bleeding should be discontinued • Activated charcoal may remove unabsorbed drug from the GI tract if given within two hours of ingestion • Unactivated prothrombin complex concentrates (PCC), • Activated PCC (eg, FEIBA) • Recombinant Factor VIIa in high doses has been suggested • Nontrivial risk of precipitating thromboembolism • Should be reserved for those with life-threatening bleeding;

28. Safety Concerns • FDA & the European Medicines Agency are currently evaluating post-marketing reports of approximately 256 serious bleeding events worldwide leading to death in patients taking Daigatran. • Median age of those with reported bleeding events in 2011 was 80 years, raising a question of safe dosing and monitoring of dabigatran in older patients, who may also have reduced renal function and other comorbidities • A meta-analysis of seven randomized trials • Use of Dabigatran (when compared with warfarin, enoxaparin or placebo controls) was associated with a significantly higher risk of myocardial infarction (MI) or acute coronary syndrome (ACS)

29. Factor XA inhibitors • Tick or leech anticoagulant proteins &their derivatives • Synthetic analogs of the heparin pentasaccharide • Orally active agents under development • Rapid onset of action • Stable pharmacodynamic profile

30. Fondaparinux (Arixtra) • Synthetic heparin pentasaccharide • Catalyzes factor Xa inactivation by AT without inhibiting thrombin • VTE prophylaxis and treatment • ACS and HIT (off label use) • No antidote is known • High doses of recombinant factor VIIa • Monitored by anti-factor X-a assays • Primarily renal clearance • Not indicated with CKD (severe)

31. Rivaroxaban (Xarelto) • Orally available with 80% bioavailability • Peak plasma concentrations occurring 2.5 to 4 hours after oral administration • Efficacy • Non-inferior efficacy VS Enoxaparin/ Vit K antagonist with respect to recurrent VTE • Major bleeding or clinically relevant nonmajor bleeding, 8.1 % of the patients in each group

32. Prevention of VTE in adults undergoing elective hip or knee replacement surgery • Fixed dosing 10mg/day, no monitoring needed • Not recommended for CrCl < 30 ml/min • Contraindicated for CrCl < 15 ml/min • Interacts with drugs that are potent inhibitors of both CYP-3A4 and P-glycoprotein efflux transporter

34. Reversal Strategies • No specific antidotes • Drug discontinuation • 90% protein bound, cannot be dialyzed • Activated charcoal may remove unabsorbed drug from the GI tract • Unactivated or activated prothrombin complex concentrates (PCC)

35. Apixaban (ELIQUIS) • Currently approved for use in Canada • US approval pending • VTE prophylaxis in total hip & knee replacement • Nonvalvular atrial fibrillation (to prevent stroke) • No antidote, cannot be dialyzed

36. Agents in development • Tissue factor & factor VII as potential targets • Recombinant form of tissue factor pathway inhibitor (TFPI) • Specific TF/FVIIa and factor VIIa inhibitors (eg, nematode anticoagulant protein) • Factor V and factor VIII as combined targets • Recombinant activated protein C • Soluble recombinant thrombomodulin

37. Factor VIII inhibitor • TB-402 (human IgG4 monoclonal antibody) • Partial inhibitor of factor VIII • Long half-life (approximately three weeks) • Phase II trial, effective antithromotic effect upto 10 days post TKR C/W Enoxaparin • Selective inhibition of the procoagulant properties of thrombin • Thrombin mutant (E229K)

38. Recombinant soluble thrombomodulin (ART-123) • Factor IXa inhibitor (REG1) • RB006, Injectable RNA aptamer that specifically binds and inhibits factor Ixa • RB007, the complementary oligonucleotide that neutralizes its anti-IXa activity if & when needed • Factor XI inhibitor • Antisense oligonucleotide targeting factor XI (mouse model) • Factor XIIa inhibitor • rHA-Infestin-4 (recombinant human albumin fused to the factor XIIa inhibitor Infestin-4)

39. To switch or not to switch • Patients already taking warfarin for atrial fibrillation with excellent INR control may have little to gain by switching to dabigatran or rivaroxaban • Dabigatran should be used with caution in patients with atrial fibrillation and signs of coronary disease, since there is some evidence for an increased risk of myocardial infarction or acute coronary syndrome

40. Patients who are poorly compliant with warfarin’s once-per day dosing may be even less compliant with dabigatran, which requires twice daily dosing. • Rivaroxaban, with a shorter half-life than dabigatran, may be equally problematic should scheduled doses be missed • Warfarin is preferred over dabigatran and rivaroxaban in those with reduced renal function (eg, creatinine clearance ≤30 mL/min)

41. Patients with GI diseases, especially those with a h/o GI bleed may not be ideal candidates for treatment with dabigatranorrivaroxaban • For patients with unexplained poor warfarin control, with a significant portion of time in sub-therapeutic INR range, the newer oral anticoagulants should be considered • However. it is critical to determine that the INR instability is not due to poor compliance. • Patients with a poor level of INR control because of unavoidable drug-drug interactions (such as frequent need for antibiotics or a large number of concomitant and variable medications) may do better with the new oral anticoagulants

42. References • http://en.wikipedia.org/wiki/Warfarin • http://en.wikipedia.org/wiki/Heparin • How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch.Sam Schulman & Mark A Crowther. Blood, 2012 119: 3016-3023 • Management of Venous Thromboembolism, past, present and future. Thomas H. Myers MD, Arch Int Med2012 119: 3016-3023

43. New drugs for thromboprophylaxis in atrial fibrillation. Pier Mannuccio Mannucci. European Journal of Internal Medicine 23 (2012) 1–5 • Actions and interactions of Antithrombin III and Heparin. Robert D. Rosenberg, MD, PhD. NEJM, Jan 16, 1975, 146-150 • Old and new anticoagulant drugs: A minireview: Pier mannuccio Mannucci 1 & Massimo Franchini, Annals of Medicine, 2011; 43: 116–123

44. Old and new oral anticoagulants for venous thromboembolism and atrial fibrillation: A review of the literature Cecilia Becattini, Maria Cristina Vedovati, Giancarlo AgnelliThrombosis Research 129 (2012) 392–400 • The potential role of new oral anticoagulants in the prevention and treatment of thromboembolism, Thomas Mavrakanas, Henri Bounameaux. Pharmacology & Therapeutics 130 (2011) 46–58

45. Parenteral Anticoagulants; American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Jack Hirsh, MD, FCCP et al, CHEST 2008; 133:141S–159S • Structure-activity relationship in heparin : a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity; J.choayl et al. BIOCHEMICAL AND BIOPHYSICALRESEARCH COMMUNICATIONS Vol. 116, No. 2, 1983, 492-499

46. The new oral anticoagulants; David Garcia et al: Blood. 2010;115:15-20 • Vitamin K Antagonists – Current Concepts and Challenges Hayan Moualla, David Garcia. Thrombosis Research 128 (2011) 210–215 • Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: ACCP Evidence-Based Clinical Practice Guidelines. Linkins LA et al. Chest.2012 Feb;141(2 Suppl):e495S-530S • UptoDate, 2012

47. Question from History • Who was the notorious 20th century dictator who was allegedly poisoned by WARFARIN ? • Hint: • Moustache • 2 million to ? Several million dead