This document summarizes the development of newer anticoagulants, including direct thrombin inhibitors and factor Xa inhibitors. It discusses the limitations of older anticoagulants like heparin, warfarin, and low molecular weight heparins. Newer oral anticoagulants like dabigatran, rivaroxaban, apixaban and edoxaban directly inhibit thrombin or factor Xa and have improved properties over warfarin such as fewer drug and food interactions and more predictable dosing without monitoring. Clinical trials found these newer anticoagulants to be as effective or more effective than warfarin or enoxaparinux for preventing strokes in atrial fibrill

1. Newer anti-coagulants13.10.11

2. Coagulation systemAvailable anticoagulants:Heparin ,LMWH ,fondaparinux, Direct thrombin inhibitors, WarfarinLimitations of established parenteral and oral anticoagulantsPotential advantages of the new agentsPharmacology and clinical trial results with new anticoagulantsConclusions and Future Directions

3. Hemostatic system The major components of the hemostatic system are:Vascular endotheliumPlateletsCoagulation system Fibrinolytic system.

4. Coagulation occurs through the action of discrete enzyme complexes, which are composed of a vitamin K–dependent enzyme and a nonenzyme cofactor.

5. Intrinsic Pathway (APTT)Factors VIII, IX, XI, and XII.

6. Activated on surface of exposed endothelium.

7. Complexes form on platelet phospholipids.Contact (Eg: with glass)XIIXIIaXIaXIIXaIXVIIIaPLCa++XXa

8. Extrinsic PathwayExtrinsic Pathway: (PT)Factors VII, IX, X

9. Activated by Tissue phospholipids (Tissue Factor or Tissue thromboplastin) released into blood as a result of tissue damage. Tissue factor (TF)VIIa- TFVIIXIaIXIXaVIIIaXaX

11. Anticoagulants – historical developmentDabigatranRivaroxabanApixaban AZD0837OralSpoiled sweet cloverWarfarinclinical useHigh / low doseWarfarin / INRXimelagatranclinical trialsDicoumaroldiscoveredWarfarin / Vitamin KmechanismWarfarinclinical trials19161924193619401950s20061970s19761980s1990s2001Heparinclinical useLMWHdiscoveredPentasaccharideclinical trialsLMWHclinical trialsHeparindiscoveredContinous heparininfusion/aPTTInjection

14. Features of an ideal anticoagulantHigh efficacy to safety indexPredictable dose responseAdministration by parenteral and oral routesRapid onset of actionAvailability of a safe antidoteFreedom from side effectsMinimal interactions

15. HeparinParenteralAnticoagulantA sulfated polysaccharideMost commercial heparin is derived from porcine intestinal mucosa Polymer of alternating d-glucuronic acid and N-acetyl-d-glucosamine residues

16. Mechanism of ActionActivates antithrombin and accelerates the rate at which it inhibits clotting enzymes, particularly thrombin and factor XaHeparin binds to the serpin via a unique pentasaccharide sequence found on one third of the chains of commercial heparin

17. Mechanism of action of heparin, LMWH, and fondaparinux

18. Side effects of heparinBleeding - the most common side effectThrombocytopeniaOsteoporosisElevated levels of transaminases.

19. Pharmacokinetic and Biophysical Limitations of Heparin

20. Low-Molecular-Weight HeparinConsists of smaller fragments of heparinLMWH is prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. The mean molecular weight of LMWH is about 5000, one third the mean molecular weight of unfractionatedheparinShorter heparin chains bind less avidly to endothelial cells, macrophages, and heparin-binding plasma proteinsThe clearance of LMWH is dose-independent and its plasma half-life is longerSituations that may require LMWH monitoring include renal insufficiency , pregnancy and obesity

21. FondaparinuxA synthetic analogue of the antithrombin-binding pentasaccharidesequenceFondaparinuxcatalyzes factor Xa inhibition by antithrombin and does not enhance the rate of thrombin inhibitionRecombinant activated factor VII reverses the anticoagulant effects of fondaparinux

22. Comparison of the Features of Heparin, Low-Molecular-Weight Heparin, and Fondaparinux

23. Advantages of Low-Molecular-Weight Heparin and Fondaparinux over Heparin

24. Direct thrombin inhibitorsHirudinRecombinant proteinsSynthetic moleculesDerived from leech (Hirudo medicinalis)

25. Recombinant hirudin (MW 6979.5 Da)

26. Bivalirudin (MW 2180 Da)

27. Argatroban(MW 527 Da)

28. Melagatran

29. Dabigatran

30. AZD0837

31. Polypeptide (65 amino acids)

32. MW 7000 Da

33. Do not require a plasma cofactor

34. Bind directly to thrombin and block its interaction with its substratesWhy thrombin is an excellent target?Forms & stabilizes the clot

35. Furthers generation of thrombin

36. Stimulates thrombus- activated fibrinolysis inhibitor (TAFI) resulting in inhibition of fibrinolysis

37. Activates plateletsDirect thrombin inhibitors – mechanism of actionThrombinExosite 1(fibrin bindingsite)ArgatrobanormelagatranActive site

38. Direct thrombin inhibitors – mechanism of actionThrombinHirudin and bivalirudinExosite 1(fibrin bindingsite)Active site

39. Parenteral Direct Thrombin Inhibitors

40. Lepirudin and argatroban are approvedfor the treatment of patients with HITBivalirudin is approved as an alternative to heparin in patients undergoing PCI, including those with HIT

41. Limitations of Existing Parenteral AnticoagulantsThe need for daily subcutaneous injection limits the long-term use of LMWH or fondaparinux. Potential for accumulation in patients with renal impairmentThe lack of an antidoteRisk of catheter thrombosis when these agents are used as the sole anticoagulant in patients undergoing PCI

42. DicoumarolPhenprocoumonWarfarin SodiumOral Anticoagulants - Vitamin K antagonistsAcenocoumarolAnisindione

43. Mechanism of ActionSome clotting factors need a carboxyl group added to their carboxyl-terminal glutamates after synthesis in the liverThis γ-carboxylation reaction requires reduced Vitamin KVitamin K epoxide is then converted back to its reduced form via the enzyme vitamin K epoxidereductase and NADHThe Vitamin K antagonists inhibit the action of the reductase enzyme

44. Effect on CoagulationIntrinsic pathwayExtrinsic pathwayXIIXIIaVIIaTFXIaXIIXaIXVIIIaVaXXaCommon pathwayII (prothrombin)IIa (thrombin)XIIIXIIIaFibrinogenFibrinStabilized Fibrin Vitamin K dependent clotting factors:Factors II, VII, IX, and X

45. WarfarinBioavailabilynearly complete; absorption dampered by foodPeak concentration 2 - 8 hrBinds to albumin 99% of timeCan cross placental barrierRacemic mixture: S form by CYP2C9; R by CYP1A2, minor pathway CYP2C19, and minor pathway CYP3A4half-life: 25 - 60 hr; Excreted in urine and stoolFood-drug & drug-drug interactions: extensive!!Toxicities: bleeding, fetal bone abnormalities, skin necrosis

46. Problems with WarfarinFood and drug interactionsGenetic variation in metabolismnarrow therapeutic windowslow onset of actiondosage adjustments & freq. monitor with INRoverlap with parenteral drugs

48. Comparison of Pharmacological Characteristics of AVE5026, Idrabiotaparinux, Otamixaban,and RB006

49. AVE5026Ultralow-molecular-weight heparin with a mean molecular weight of 2400Primarily targets fXaGiven subcutaneously, the half-life is 16 to 20 hours, enabling once-daily administration. Excreted renallyAnticoagulant effects are not neutralized by protaminesulfatePhase III program comparing AVE5026 with enoxaparin for VTE prevention in 9000 patients undergoing hip, knee, or abdominal surgery and in 3200 cancer patients receiving chemotherapy is ongoing(SAVE-HIP2 , SAVE-ABDO, SAVE-KNEE , SAVE-HIP3 , SAVE-ONCO

50. IdrabiotaparinuxHypermethylated derivative of fondaparinuxBinds antithrombin with high affinity Has a half-life of 130 hours; idrabiotaparinux is given subcutaneously on a once-weekly basis. Excreted unchanged by the kidneys. Differs from idraparinuxin that it contains a biotin moiety that enables reversal with intravenous avidin

51. The Van Gogh deep vein thrombosis (DVT) trial compared 3 to 6 months of idraparinux with conventional anticoagulant therapy in 2904 patients with acute DVT.At 3 months, the incidence of recurrent VTE (nonfatal or fatal) was similar in the 2 treatment groupsIdraparinuxwas associated with significantly fewer major plus clinically relevant nonmajor bleeds than conventional therapyThe AMADEUS trial compared idraparinux with a VKA for prevention of thromboembolism in patients with AF. The trial was stopped early because of an excess of clinically relevant bleeds with idraparinux compared with a VKAEQUINOX bioequivalence study suggested that idrabiotaparinux and idraparinux are similarly effective for DVT treatmentCASSIOPEA trial is comparing 3 to 6 months of idrabiotaparinux with conventional anticoagulation therapy for prevention of recurrent VTE

52. OtamixabanA parenteral direct fXainhibitorHas a rapid onset of actionproduces a predictable anticoagulant effectHas a short half-life25% of the drug is cleared by the kidneys.These features render otamixaban an attractive candidate to replace heparin in patients with ACSSEPIA-ACS 1(TIMI) 42, a phase II dose-finding study that compared 5 different doses of otamixabanwith the combination of heparin plus eptifibatide in 3241 patients with non–ST-segment elevation ACS

53. RB006An RNA aptamerthat targets factor IXa with high affinity and specificity, When given intravenously, produces a rapid and dose-proportional anticoagulant effect Immediately reversed by intravenous administration of RB007, the complementary oligonucleotide antidote.RB006 is not cleared renallydoes not appear to be immunogenichas the potential to inhibit the activation of coagulation induced by exposure of blood to artificial surfaces, such as stents or cardiac bypass circuitspotential to replace heparin and protaminesulfate in patients undergoing cardiopulmonary bypass surgery. May also be useful for patients at high risk of bleeding and for those with renal impairmentPhase II REVERSAL-PCI study, the efficacy and safety of RB006/RB007 are being compared with those of heparin in 26 patients undergoing elective PCI

55. Oral Thrombin Inhibitors

56. DabigatranEtexilatea prodrug of dabigatran, which reversibly inhibits the active site of thrombinhas an oral bioavailability of 6%Plasma levels of dabigatran peak 2 hours after drug administration. Dabigatranhas a half-life of 14 to 17 hours, which permits once- or twice-daily administration80% of the drug is excreted unchanged by the kidneysCoadministration of dabigatranetexilate and amiodarone, a weak P-gp inhibitor, increases dabigatran levels by 50% without significantly affecting those of amiodarone

57. Dabigatranetexilatein VTEDabigatranetexilate is approved for VTE prevention after elective hip or knee arthroplasty. 220-mg dose of dabigatranetexilate is recommended for the majority of patients150-mg dose is reserved for patients also taking amiodarone and for those at higher risk for bleedingRECOVER-1 in acute VTEdabigatranetexilateor warfarinfor 6 months after initial treatment with a parenteral anticoagulant.recurrent symptomatic VTE and VTE-related death, were 2.4% and 2.1% in dabigatranand warfarin groups, respectively Rates of major bleeding were 1.6% and 1.9% in the dabigatran and warfarin groups, respectively

58. Dabigatranetexilate in AFThe RE-LY trial randomized 18 113 patients with AF and at least 1 additional risk factor for stroke to receive dabigatranetexilate (at doses of 110 or 150 mg twice daily) or warfarinDabigatran110 mg b.i.d. was non-inferior to VKA for the prevention of stroke and systemic embolism with lower rates of major bleedingDabigatran 150 mg b.i.d. was associated with lower rates of stroke and systemic embolism with similar rates of major haemorrhage, compared with VKA.

59. Dabigatranetexilate in ACSDabigatranetexilate has also been evaluated in the phase II RE-DEEM study in ACS to determine whether it reduces the risk of recurrent ischemia when given in conjunction with antiplatelet drugs

60. Oral fXa Inhibitors:Rivaroxaban, apixaban and edoxaban

61. RivaroxabanAn active compound with an oral bioavailability of 80%Has a rapid onset of action and a half-life of 7 to11 hours.Has a dual mode of eliminationconcomitant administration of potent inhibitors or both P-gp and CYP3A4 is contraindicatedOn the basis of the results of RECORD trials, rivaroxaban is approved for the prevention of VTE in patients undergoing elective hip or knee arthroplasty

62. ROCKET AFPrimary Efficacy OutcomeStroke and non-CNS EmbolismWarfarinRivaroxabanCumulative event rate (%)HR (95% CI): 0.79 (0.66, 0.96)P-value Non-Inferiority: <0.001Days from RandomizationNo. at risk:Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655Event Rates are per 100 patient-yearsBased on Protocol Compliant on Treatment Population

63. Summary ROCKET AFEfficacy:Rivaroxabanwas non-inferior to warfarin for prevention of stroke and non-CNS embolism.Rivaroxaban was superior to warfarin while patients were taking study drug.By intention-to-treat, rivaroxaban was non-inferior to warfarin but did not achieve superiority.Safety:Similar rates of bleeding and adverse events.Less ICH and fatal bleeding with rivaroxaban.Conclusion:Rivaroxaban is a proven alternative to warfarin for moderate or high risk patients with AF.

64. Rivaroxaban in ACS phase-3 ATLAS-ACS 2 TIMI 51 clinical trial of rivaroxaban ACS patients has met its primary efficacy end pointstatistically significant reduction in the primary composite end point of cardiovascular death, MI, and stroke vs placebo. significant increase in the primary safety end point: major bleeding events not associated with coronary artery bypass surgeryThe ATLAS-ACS 2 TIMI 51 results will be presented as a late-breaking clinical trial at the American Heart Association 2011 Scientific Sessions in Orlando

65. ApixabanAn active drugabsorbed rapidlyMaximal plasma concentrations are achieved 3 hours after oral administration.half-life of 8 to14 hours. eliminated via multiple pathwaysConcomitant treatment with potent inhibitors of CYP3A4 is contraindicated

66. Pooled data from the ADVANCE clinical-trial program showed that apixaban is more effective than enoxaparin for the prevention of major VTEin patients undergoing hip- or knee-replacement surgery

67. AVERROES

69. ARISTOTLE study

70. ARISTOTLE study

71. APPRAISE-2 ACS trial the phase 3 APPRAISE-2 trial of apixaban in high-risk patients with recent acute coronary syndrome discontinuedafter it became clear that the increase in bleeding risk in patients randomized to apixaban would not be offset by reductions in ischemic events

72. Edoxabanactive drug rapidly absorbedhalf-life of 9 to 11 hours dual mechanism of eliminationENGAGE-AF-TIMI 48 trial is comparing 2 doses of edoxaban (30 or 60 mg once daily) with warfarin in 16 500 patients with AF

73. Other oral fXa inhibitors under development include betrixaban(15-hour half-life and extrarenal clearance)