Newer anticoagulants

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Newer anticoagulants

  1. 1. NEWER ANTICOAGULANTS-Dr.Deep Chandh Raja(as on Feb’2013)
  2. 2. SYNOPSIS• OVERVIEW OF COAGULATION CASCADE• CONTEMPORARY ANTICOAGULANTS & THEIRDISADVANTAGES• “IDEAL” ANTICOAGULANT• SPECTRUM OF NEWER ANTICOAGULANTS• PRESENT INDICATIONS OF NEWERANTICOAGULANTS• FUTURE OF ANTICOAGULATION
  3. 3. • COAGULATION-“A DEFENCE MECHANISM of the body”ANTI-COAGULANTSCOAGULANTS
  4. 4. VIRCHOW’S TRIAD
  5. 5. CLINICAL EXAMPLES OFDISTURBANCES IN VIRCHOW’S TRIAD• HYPERTENSION• ENDOTOXINS• ULCERATED ATHEROSCLEROTIC PLAQUES• ANEURYSMS• PROSTHESIS• DILATED LEFT ATRIUM• FACTOR V MUTATIONS• APLS SYNDROME• HIT SYNDROME
  6. 6. FORMATION OF “BLOOD CLOT”• Platelet adhesion• Platelet aggregation• “Trap” ofcoagulation factors• Clot formation• Clot stabilisation(Fibrin formation)• Clot resolutionANTIPLATELETSANTICOAGULANTSTHROMBOLYTICS
  7. 7. THROMBIN- The ANCHOR !
  8. 8. The Common Pathway
  9. 9. xx
  10. 10. ANTICOAGULANTS- “Blood Thinners”
  11. 11. • ‘Fixed’ ‘oral’ dose• No need for dose adjustment• Wide therapeutic range• Acceptable bleeding risks• No need for monitoringAN “IDEAL” ANTI COAGULANT
  12. 12. Indications of Anticoagulant Therapy• Prevention and Treatment of Deep VenousThrombosis• Treatment of Pulmonary Emboli• Prevention of stroke in patients with atrialfibrillation, artificial heart valves, establishedthrombosis (DVT, Cardiac)• Ischaemic heart disease• During procedures such as cardiac catheterisation
  13. 13. EVIDENCE BASED MEDICINE
  14. 14. CONTEMPORARY ANTICOAGULANTSPARENTERAL• UNFRACTIONATED HEPARIN(HMWH)• LOW MOLECULAR WEIGHTHEPARIN (LMWX)ORAL• WARFARIN
  15. 15. NEWER ANTICOAGULANTSPARENTERAL• FONDAPARINUX• INDRAPARINUX• LEPIRUDIN• ARGATROBAN• BIVALURIDINORAL• RIVAROXABAN• APIXABAN• XIMELAGATRAN• DABIGATRAN
  16. 16. CLASSIFICATION BASED ONMECHANISM OF ACTION
  17. 17. THROMBIN INHIBITORSCONTEMPORARY• HMWH• LMWHNEWER-NONE- • LEPIRUDIN• ARGATROBAN• BIVALURIDIN• XIMELAGATRAN• DABIGATRANPARENTERAL ORALINDIRECT THROMBIN INHIBITORS DIRECT THROMBIN INHIBITORS
  18. 18. FACTOR Xa INHIBITORSLMWHHMWH •FONDAPARINUX• INDRAPARINUX•RIVAROXABAN• APIXABANINDIRECT DIRECTCONTEMPORARY NEWER ANTICOAGULANTS
  19. 19. VITAMIN K ANTAGONIST• Only one drug which has a rich history and the center ofmany controversies !• But still the only dispensable option all over the years !• WARFARIN
  20. 20. CLASSIFICATION BASED ON MODE OFADMINISTRATION
  21. 21. PARENTERAL ANTICOAGULANTSCONTEMPORARY• UNFRACTIONATED HEPARIN(HMWH)• LOW MOLECULAR WEIGHTHEPARIN (LMWX)NEWER• FONDAPARINUX• INDRAPARINUX• LEPIRUDIN• ARGATROBAN• BIVALURIDIN
  22. 22. NO ONE PREFERSAN INJECTION !!!
  23. 23. ORAL ANTICOAGULANTSCONTEMPORARY• WARFARINNEWER• RIVAROXABAN• APIXABAN• XIMELAGATRAN• DABIGATRAN….a lot more..
  24. 24. New and Emerging Anticoagulants• Anti – Xa : direct– Rivaroxaban (oral)– Apixaban (oral)– Betrixiban (oral)– Edoxaban (oral)– Otamixaban (parenteral)– LY – 517717 (oral)– DU – 176B (oral)– DX – 9065a (parenteral)– PRT054021 (oral)• Anti – Xa : indirect– Idraparinux biotinylated(parenteral)• Anti – IIa– Dabigatran (oral)– Odiparcil (oral)– Flovagatran (parenteral)– Pegmusirudin (parenteral)– Peg Hirudin– Desiruidin– Ximelgatran
  25. 25. THE INDIVIDUAL DRUGS !!!1. WHY LMWH OVER HMWH ???2. WHY NOT WARFARIN ???
  26. 26. THE HEPARINS
  27. 27. Heparin mechanism of actionHeparinAntithrombin IIIThrombin
  28. 28. THE HEPARINS !!!• HMWH- long chains• LMWH- short chains• ‘PARINUX’-very shortspecific sequencesHMWHLMWH PARINUX
  29. 29. HMWH vs LMWHHMWH• Dose dependentclearance• Low bioavailability• Short t 1/2• Unpredictable response• Close monitoring• H.I.T• Bleeding• Osteoporosis• Extrarenal clearanceLMWH
  30. 30. WARFARIN & ITS PROBLEMS !
  31. 31. WarfarinWarfarinSynthesis of NonSynthesis of NonFunctionalFunctionalCoagulationCoagulationFactorsFactorsAntagonismofVitamin KWarfarin Mechanism of ActionVitamin KVitamin KVIIVIIIXIXXXIIII
  32. 32. DISADVANTAGES• RESISTANCE(Cyt 2C9 & VKOR C1 enzymes)• Diet interference• Disease states• Drug interactions• Narrow therapeutic window• Slow onset of action• Skin necrosis• Bleeding• Pregnancy• APLS syndrome
  33. 33. Warfarin-induced Skin Necrosis
  34. 34. THE NEWER ANTICOAGULANTS !!!
  35. 35. FONDAPARINUX
  36. 36. Properties• Complete bioavailability• Plasma t 1/2- 17 hours• Subcutaneous once daily dosing• Renal clearance• Prophylactic dosing- 2.5 mg once daily• Therapeutic dosing- 7.5 mg once daily• H.I.T does not occur• Bleeding risks equal to LMWH
  37. 37. Idraparinux• Once weekly SC injection• 100% SC bioavailability• Half-life ~ 96-130 hours• Renal elimination• No monitoring required• FAILED APPROVAL BYTHE US FDA
  38. 38. LEPIRUDIN, ARGATROBAN• Parenteral Direct Thrombin Inhibitors• Lepirudin-i.v infusion, t ½ of 60 minutes, renal clearance• Argatroban-i.v infusion, t ½ of 45 minutes, hepatic clearance
  39. 39. BIVALURIDIN• Divalent thrombin inhibitor• Shortest half life of all DTIs- 20 minutes• Degraded by peptidases• i.v infusions• Significantly less bleeding
  40. 40. Rivaroxaban• Oral tablet• Factor Xa inhibitor• High oral bioavailability(>80%)• Onset of action 2-4 hours• Half-life 9-12 hours• No observed effects onagonist-induced plateletaggregation• Primarily renal elimination• No laboratory monitoringrequired• No dosage adjustment forgender, age, extreme bodyweight• Approved by Europe andCanadian agencies, andFDA
  41. 41. Rivaroxaban in VTE Prevention:RECORD 3 - TKA02468101214161820Rivarox 10Qday x 14 dEnox 40 Qdayx 14 daysComposite Major VTE0123456Rivarox 10QdayEnox 40 QdayMajor Bleed Any Bleed%RRR49%RRR62%%No Difference2531 patients
  42. 42. Rivaroxaban in VTE Prevention:RECORD 4 - TKA3034 patients0246810Rivarox 10 mgQdayEnox 30 mg BIDCompositeSymptomatic VTE and all-cause mortality00.511.522.533.5Rivarox 10 mgQdayEnox 30 mg BIDMajor Bleed Any Bleed%%Turpie, et al. Lancet 2009;373:1673 – 80.Not SignificantRivarox: RRR31%; ARR 3.2%
  43. 43. ROCKET-AF TRIAL
  44. 44. Rivaroxaban OngoingClinical TrialsDVTEinstein-DVTRivarox 15mg BID x 3wks then 20mg QdayvsEnox/VKAPEEinstein-PERivarox 15mg BID x 3wks then 20mg QdayvsEnox/VKAMedically IllRivarox 10mg Qday x 35 daysvsEnox 40mg Qday x 10 daysDVT/PEEinstein-ExtensionRivarox 20mg QdayvsPlacebo
  45. 45. Apixaban• Oral tablet• Bioavailability: 50%• Peak Plasma Levels = 3 hrs• Half-life ~ 12 hours• Metabolized in liver viaCYP3A4 and CYPindependent mechanisms• Eliminated via multiplepathways• No laboratorymonitoring required• Has been submitted forapproval by the US FDA
  46. 46. Apixaban EfficacyOutcomes in TKR05101520253035405QDay10QDay20QDayEnox30mg BID(n=152)Warf(n=153)2.5BID5BID10BIDApixaban (mg) (n = 933)Incidence of VTE and all-cause death (%)Duration =10 -14 daysLassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.
  47. 47. Apixaban SafetyOutcomes in TKR0246810121416185QDay10QDay20QDayEnox30mg BID(n=152)2.5BID5BID10BIDApixaban (mg) (n = 933)Warf(n=153)Incidence of bleeding events (%)
  48. 48. Summary of ADVANCE – 2 TRIAL• Apixaban 2.5mg BID vs. Enoxaparin 40mg QD• Superior for:– Primary endpoint of ANY DVT/PE/All-Cause Death– Secondary endpoint for Major VTE• Lower observed bleeding rates– Major– Clinically relevant non-major• Similar overall safety profile
  49. 49. Ximelagatran• First target-specific oral anticoagulant in trials• Ximelagatran is the oral prodrug of Melagatran• Hepatatoxicity– Did not receive FDA approval in 2004– On the market in Europe but pulled in 2006• ‘proof of principle’– “efficacious” as warfarin– Wider therapeutic index– Little dosage adjustment/ no monitoring
  50. 50. Dabigatran Etexilate• Potent and reversible oral Direct Thrombin Inhibitor• Inhibiting both clot bound and free thrombin• Predictable and consistent PK profile-Rapid onset/offset ofaction (Peak plasma levels within 2 hours)• Anticoagulation monitoring—Not required• Half-life 12–17 hours (twice-daily dosing)• Low drug–drug interactions (not metabolised by CYP450enzymes) However, P glycoprotein inhibitors Amiodarone,verapamil and quinidine may increase its plasma level• No food–drug interactions reported• Dosing independent of meals or dietary restrictions• 65% bioavailability, ~80% renal excretion
  51. 51. TRIALS IN PREVENTION OF DVT• RE-MOBILISE• RE-NOVATE• RE-MODEL“Dabigatran was non inferior to enoxaparin interms of efficacy and bleeding risks”
  52. 52. Dabigatran:Acute VTETreatmentRE-COVERAF andStrokePreventionRE-LYSecondary VTEPreventionRE-MEDY# Patients# Patients 25542554 1800018000 20042004Study ArmsStudy ArmsDabigatranDabigatran150 mg BID150 mg BIDvsvswarfarinwarfarinDabigatranDabigatran100 mg BID100 mg BIDand 150 mgand 150 mgBIDBIDvsvswarfarinwarfarinDabigatranDabigatran150 mg BID150 mg BIDvsvswarfarinwarfarin
  53. 53. What about RE-LY?Dabigatran versus Warfarin in Patients withAtrial Fibrillation• Non-inferiority trial• Over 18,000 patients• Followup = 2 yearsDabigatran 110 mg and 150mgDabigatran 110 mg and 150mgvs.vs.Adjusted dose warfarinAdjusted dose warfarin
  54. 54. Incidence of Stroke or Systemic EmbolismRR 0.65 (95% CI: 0.52–0.81)Stroke/systemicembolism(%/yr)Events/n:BID, twice daily; NI, non-inferiority; RR, relative risk; RRR , relative risk reduction; Sup, superiorityConnolly SJ, et al. N Engl J Med. 2010;363:1875–1876.183/6015 134/6076 202/6022Dabigatran110 mg BIDDabigatran150 mg BIDWarfarin0.00.30.60.91.21.51.81.541.111.71P<.001 (Sup)P<.001 (NI)RR 0.90 (95% CI: 0.74–1.10)RRR35%
  55. 55. Events/n:BID, twice daily; RR, relative risk; RRR, relative risk reduction; Sup, superiorityConnolly SJ et al. NEJM 2009; 361 (12): 1139-1151.27/6015 36/6076 87/6022Dabigatran110 mg BIDDabigatran150 mg BIDWarfarin00.60.9Intracranialbleeding(%/yr)0.80.70.50.40.30.20.10.230.300.74RR 0.31(95% CI:0.20–0.47)P<.001 (Sup)RR 0.40 (95% CI: 0.27–0.60)P<.001 (Sup)RRR69%RRR60%Significantly Lower Intracranial Bleeding with Dabigatran
  56. 56. Most Common Adverse EventsAdverse event (%)Dabigatran110 mg BIDDabigatran150 mg BIDWarfarinDyspepsia* 11.8 11.3 5.8Dyspnoea 9.3 9.5 9.7Dizziness 8.1 8.3 9.4Peripheral oedema 7.9 7.9 7.8Fatigue 6.6 6.6 6.2Cough 5.7 5.7 6.0Chest pain 5.2 6.2 5.9Arthralgia 4.5 5.5 5.7Back pain 5.3 5.2 5.6Nasopharyngitis 5.6 5.4 5.6Diarrhoea 6.3 6.5 5.7Urinary tract infection 4.5 4.8 5.6Upper respiratory tractinfection4.8 4.7 5.2Adverse events occurring in >5% of patients in any treatment group; *Occurred more commonly with dabigatran, P<.001;BID, twice dailyTablereproducedwithpermission:©2009MassachusettsMedicalSociety
  57. 57. PropertyProperty RivaroxabanRivaroxaban ApixabanApixaban IdraparinuxIdraparinux DabigatranDabigatranTargetTarget Factor XaFactor Xa Factor XaFactor Xa Factor XaFactor Xa(indirect)(indirect)ThrombinThrombinROAROA OralOral OralOral SubcutaneousSubcutaneous OralOralProdrugProdrug NoNo NoNo YesYes YesYesBioavailabilityBioavailability > 80%> 80% > 50%> 50% 100%100% 6%6%Time to peakTime to peak 33 33 ______ 22Half-lifeHalf-life 9 hrs9 hrs 9 – 14 hrs9 – 14 hrs 80 hrs80 hrs 14 – 17 hrs14 – 17 hrsFrequency ofFrequency ofAdministrationAdministrationQdayQday BIDBID Q WeekQ Week Qday or BIDQday or BIDDrugDrugInteractionsInteractionsPotent CYP3A4 &Potent CYP3A4 &P-glycoproteinP-glycoproteininhibitorsinhibitorsPotent CYP3A4 &Potent CYP3A4 &P-glycoproteinP-glycoproteininhibitorsinhibitors______ P-glycoproteinP-glycoproteininhibitorsinhibitorsRenal excretionRenal excretion 66%66% 25%25% YesYes 80%80%Safe inSafe inpregnancypregnancyNoNo NoNo UnknownUnknown NoNoAntidoteAntidote NoNo NoNo NoNo NoNoAdapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.
  58. 58. INDICATIONS OF NEWERANTICOAGULANTS
  59. 59. PREVENTION OF DVTPrinciples of treatment• HMWH• LMWH• WarfarinNEWER• Fondaparinux• Dabigatran 220 mg bd(Post THR, TKR)• Rivaroxaban 10 mg qd(Post THR, TKR)• In critically illpatients• Post THR, TKR• Orthopedic &other surgeries• Medicalconditions likepost MI, StrokeCONTEMPORARY
  60. 60. TREATMENT OF DVTPrinciples of treatment• HMWH80 U/kg STAT f/b18 U/kg/hrinfusion• LMWHNEWER• Fondaparinux• Dabigatran awaitsapproval by US FDA• Anti thrombotics-a must• Decision to betaken reg. IVCfilters• 2nd VTE,unprovoked VTE &cancer associatedVTE-indefiniteduration• Else- 3-6 monthsdurationCONTEMPORARY
  61. 61. TREATMENT OF PULMONARY EMBOLISMPrinciples of treatment• HMWH80 U/kg stat f/b18 U/kg/hrinfusion• LMWHNEWER• Fondaparinux• Other trials areongoing….• Presence of RVdysfunction /hemodynamicinstabilityThrombolysis• Small tomoderate PE-antithrombotics• Well’s criteria> 3-antithromboticsCONTEMPORARY
  62. 62. PREVENTION OF STROKE IN AF
  63. 63. Why do we need long termanticoagulation ?• Atrial fibrillation (AF) is responsible for one-third of all strokesand is the leading cause of embolic stroke• Stroke is the most serious complication of AF• There is 5 foldand 17 foldincrease in the risk of stroke due tonon-valvular AF (NVAF) and valvular AF respectively• About one in four people at age 55 years will go on to developAF (24% of men and 22% of women)• 1 in 20 (5%) AF patients can have a stroke if not prevented• In excess of 7% per year can be attributed to rate of brainischemia due to transient ischemic attacks and clinically ‘silent’strokes, associated with Non valvular Atrial Fibrillation
  64. 64. PREVENTION OF STROKEIN ATRIAL FIBRILLATION• CLASS 1 INDICATIONS:1.Presence of cardiac thrombus / DVT2.In AF due to valvular causes3.In AF due to non valvular causes(as per CHADS2 score)
  65. 65. Choice In AF due to non valvular causes(as per CHADS2 score)• 1= aspirin /anticoagulant• >1=anticoagulant
  66. 66. PREVENTION OF STROKEPrinciples of treatment• HMWH• LMWHNEWER• FONDAPARINUX• DABIGATRAN110/150 mg BD• RIVAROXABAN20 mg QD• APIXABAN awaitsapproval by US FDA• In AF• Mechanical heartvalves• Incardiomyopathies• Inheritedcoagulopathies• DVTCONTEMPORARY
  67. 67. 150 mg OR 110 mg DABIGATRAN ?150 mg 110 mg< 75 years1, 2≥ 75 years1, 2with risk factors:(i) Higher risk for bleed*(ii)Pharmacodynamic interactions**(iii)Factors increasing dabigatran plasmalevels***1, 2Superior vs warfarin for stroke1, 2Noninferior vs warfarin for stroke1, 2Noninferior vs warfarin for risk of majorbleed1, 2 –Superior vs warfarin for ICHSuperior vs warfarin for risk of major bleed1, 2Superior vs warfarin for ICH*1. Congenital or acquired coagulation disorders, 2.Thrombocytopenia or functional platelet defects, 3.Active ulcerative gastrointestinal(GI) disease, 4.Recent GI bleeding, 5.Recent biopsy or major trauma, 6.Recent intracranial hemorrhage, 7.Brain, spinal or ophthalmicsurgery, 8.Bacterial endocarditis**Acetylsalicylic acid, NSAID, Clopidogrel***Moderate renal impairment (30-50ml/min CrCL), P- glycoprotein-inhibitor comedication
  68. 68. Prevention of Atrial Fibrillation-Related Stroke
  69. 69. 76The Newer Anticoagulants on theHorizonTrial Drug Dose Comparator NCHADS2scoreRE-LY Dabigatran150 mg and110 mg*BIDWarfarin(INR 2.0–3.0)18,113 >0ROCKET-AF5,6Rivaroxaban20 mg*ODWarfarin(INR 2.0–3.0)14,264 ≥2AVERROES3,4Apixaban5 mgBIDAspirin(81–324 mg OD)6000 ≥1ARISTOTLE1,2Apixaban5 mgBIDWarfarin(INR 2.0–3.0)18,201 ≥1ENGAGE-AF TIMI487Edoxaban30 mg OD60 mg ODWarfarin(INR 2.0–3.0)>20,000 ≥2*Adjusted based on renal function. BID, twice daily; INR, international normalised ratio; OD, once daily
  70. 70. PREVENTION OF STROKEIN NON CARDIOEMBOLIC EVENTS“No evidence that warfarin is superior toaspirin in stroke prevention”Evidence based on the following landmark trials-•WATCH- low ef CHF•APASS- APLS syndrome pts.•PICSS- Patent foramen ovale pts.•WARSS trials
  71. 71. IN H.I.T SyndromesWithdraw heparin and initiate one of thefollowing:•Lepirudin – preferred over Argatroban in hepaticdiseases•Argatroban- preferred over lepirudin andfondaparinux in renal diseases•Fondaparinux“Warfarin NOT TO BE USED IMMEDIATELY postHMWH/LMWH”
  72. 72. Pre Cardiac catherisation (PCI)• LMWH / Bivaluridin preferred post MI
  73. 73. Potential Limitations of NewAnticoagulants• Antidotes– None of the newer agents has a specific antidote• Monitoring• Adverse Drug Events• Compliance• Cost• Clinical Trials vs. Actual Clinical Practice• Patient populations not even studied (i.e. Cancer)
  74. 74. FUTURE OF ANTI COAGULATION
  75. 75. SummaryDabigatranRivaroxabanApixabanTime to Market for New Anti-Thrombotic Agents2010 2011 2012 2013Otomaxiban
  76. 76. AnticoagulantsAnticoagulants• CURRENT DRUGS– Unfractionated Heparin______________– Low Molecular Weight Heparin________– Lepirudin (DTI)____________________– Bivalirudin (DTI) ___________________– Argatroban(DTI)____________________– Danaparoid_______________________– Drotrecogin Alfa____________________– Vitamin K antagonists (Warfarin)_______• NEW/ in DEVELOPMENT DRUGS– Fondaparinux_____________________– Idraparinux_______________________– SSR 126517______________________– Rivaroxaban______________________– Apixaban_________________________– LY517717________________________– YM150__________________________– DU-176b_________________________– Betrixaban________________________– Ximelagatran*_____________________– Dabigatran etexilate________________*taken off the market Italics are Oral DrugsTARGETED FACTORAntithrombin (indirectly Xa and IIa)Antithrombin (indirectly Xa and IIa)Thrombin (IIa)Thrombin (IIa)Thrombin (IIa)AntithrombinVa, VIIIaProthrombin (II), VII, IX, XXaXaXaXaXaXaXaXaXaThrombin (IIa)Thrombin (IIa)
  77. 77. • “HAD WARFARIN INTRODUCED INTO THEMARKET TODAY, THE US FDA WOULD HAVEREJECTED”-A FAMOUS CARDIOLOGIST DURING THE ESC“BUT STILL, WARFARIN REMAINS OUR POOR MAN’S CHOICE”
  78. 78. THANK YOU !!!

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