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Newer anticoagulants
This document summarizes newer anticoagulants that are alternatives to traditional agents like heparin and warfarin. It discusses the mechanisms and properties of newer oral anticoagulants like rivaroxaban and dabigatran which directly inhibit thrombin or Factor Xa. Clinical trials showed these drugs were as effective as enoxaparin or warfarin for preventing blood clots after knee or hip surgery with lower rates of bleeding complications. The RE-LY trial found dabigatran 150mg twice daily reduced strokes by 35% compared to warfarin in atrial fibrillation patients.
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Newer anticoagulants
- 1. NEWER ANTICOAGULANTS -Dr.Deep ChandhRaja (as on Feb’2013)
- 2. SYNOPSIS • OVERVIEW OFCOAGULATION CASCADE • CONTEMPORARY ANTICOAGULANTS & THEIR DISADVANTAGES • “IDEAL” ANTICOAGULANT • SPECTRUM OF NEWER ANTICOAGULANTS • PRESENT INDICATIONS OF NEWER ANTICOAGULANTS • FUTURE OF ANTICOAGULATION
- 3. • COAGULATION- “A DEFENCEMECHANISM of the body” ANTI- COAGULANTS COAGULANTS
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- 5. CLINICAL EXAMPLES OF DISTURBANCESIN VIRCHOW’S TRIAD • HYPERTENSION • ENDOTOXINS • ULCERATED ATHEROSCLEROTIC PLAQUES • ANEURYSMS • PROSTHESIS • DILATED LEFT ATRIUM • FACTOR V MUTATIONS • APLS SYNDROME • HIT SYNDROME
- 6. FORMATION OF “BLOODCLOT” • Platelet adhesion • Platelet aggregation • “Trap” of coagulation factors • Clot formation • Clot stabilisation (Fibrin formation) • Clot resolution ANTIPLATELETS ANTICOAGULANTS THROMBOLYTICS
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- 13. • ‘Fixed’ ‘oral’dose • No need for dose adjustment • Wide therapeutic range • Acceptable bleeding risks • No need for monitoring AN “IDEAL” ANTI COAGULANT
- 14. Indications of AnticoagulantTherapy • Prevention and Treatment of Deep Venous Thrombosis • Treatment of Pulmonary Emboli • Prevention of stroke in patients with atrial fibrillation, artificial heart valves, established thrombosis (DVT, Cardiac) • Ischaemic heart disease • During procedures such as cardiac catheterisation
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- 16. CONTEMPORARY ANTICOAGULANTS PARENTERAL • UNFRACTIONATEDHEPARIN (HMWH) • LOW MOLECULAR WEIGHT HEPARIN (LMWX) ORAL • WARFARIN
- 17. NEWER ANTICOAGULANTS PARENTERAL • FONDAPARINUX •INDRAPARINUX • LEPIRUDIN • ARGATROBAN • BIVALURIDIN ORAL • RIVAROXABAN • APIXABAN • XIMELAGATRAN • DABIGATRAN
- 18. CLASSIFICATION BASED ON MECHANISMOF ACTION
- 19. THROMBIN INHIBITORS CONTEMPORARY • HMWH •LMWH NEWER -NONE- • LEPIRUDIN • ARGATROBAN • BIVALURIDIN • XIMELAGATRAN • DABIGATRAN PARENTERAL ORAL INDIRECT THROMBIN INHIBITORS DIRECT THROMBIN INHIBITORS
- 20. FACTOR Xa INHIBITORS LMWH HMWH• FONDAPARINUX • INDRAPARINUX • RIVAROXABAN • APIXABAN INDIRECT DIRECT CONTEMPORARY NEWER ANTICOAGULANTS
- 21. VITAMIN K ANTAGONIST •Only one drug which has a rich history and the center of many controversies ! • But still the only dispensable option all over the years ! • WARFARIN
- 22. CLASSIFICATION BASED ONMODE OF ADMINISTRATION
- 23. PARENTERAL ANTICOAGULANTS CONTEMPORARY • UNFRACTIONATEDHEPARIN (HMWH) • LOW MOLECULAR WEIGHT HEPARIN (LMWX) NEWER • FONDAPARINUX • INDRAPARINUX • LEPIRUDIN • ARGATROBAN • BIVALURIDIN
- 24. NO ONE PREFERS ANINJECTION !!!
- 25. ORAL ANTICOAGULANTS CONTEMPORARY • WARFARIN NEWER •RIVAROXABAN • APIXABAN • XIMELAGATRAN • DABIGATRAN ….a lot more..
- 26. New and EmergingAnticoagulants • 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
- 27. THE INDIVIDUAL DRUGS!!! 1. WHY LMWH OVER HMWH ??? 2. WHY NOT WARFARIN ???
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- 29. Heparin mechanism ofaction Heparin Antithrombin III Thrombin
- 30. THE HEPARINS !!! •HMWH- long chains • LMWH- short chains • ‘PARINUX’-very short specific sequences HMWH LMWH PARINUX
- 31. HMWH vs LMWH HMWH •Dose dependent clearance • Low bioavailability • Short t 1/2 • Unpredictable response • Close monitoring • H.I.T • Bleeding • Osteoporosis • Extrarenal clearance LMWH
- 32. WARFARIN & ITSPROBLEMS !
- 33. WarfarinWarfarin Synthesis of NonSynthesisof Non FunctionalFunctional CoagulationCoagulation FactorsFactors Antagonism of Vitamin K Warfarin Mechanism of Action Vitamin KVitamin K VIIVII IXIX XX IIII
- 35. 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
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- 39. 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
- 40. Idraparinux • Once weeklySC injection • 100% SC bioavailability • Half-life ~ 96-130 hours • Renal elimination • No monitoring required • FAILED APPROVAL BY THE US FDA
- 41. LEPIRUDIN, ARGATROBAN • ParenteralDirect Thrombin Inhibitors • Lepirudin- i.v infusion, t ½ of 60 minutes, renal clearance • Argatroban- i.v infusion, t ½ of 45 minutes, hepatic clearance
- 42. BIVALURIDIN • Divalent thrombininhibitor • Shortest half life of all DTIs- 20 minutes • Degraded by peptidases • i.v infusions • Significantly less bleeding
- 43. Rivaroxaban • Oral tablet •Factor Xa inhibitor • High oral bioavailability (>80%) • Onset of action 2-4 hours • Half-life 9-12 hours • No observed effects on agonist-induced platelet aggregation • Primarily renal elimination • No laboratory monitoring required • No dosage adjustment for gender, age, extreme body weight • Approved by Europe and Canadian agencies, and FDA
- 44. Rivaroxaban in VTEPrevention: RECORD 3 - TKA 0 2 4 6 8 10 12 14 16 18 20 Rivarox 10 Qday x 14 d Enox 40 Qday x 14 days Composite Major VTE 0 1 2 3 4 5 6 Rivarox 10 Qday Enox 40 Qday Major Bleed Any Bleed % RRR 49% RRR 62% % No Difference 2531 patients
- 45. Rivaroxaban in VTEPrevention: RECORD 4 - TKA 3034 patients 0 2 4 6 8 10 Rivarox 10 mg Qday Enox 30 mg BID Composite Symptomatic VTE and all-cause mortality 0 0.5 1 1.5 2 2.5 3 3.5 Rivarox 10 mg Qday Enox 30 mg BID Major Bleed Any Bleed % % Turpie, et al. Lancet 2009;373:1673 – 80. Not Significant Rivarox: RRR 31%; ARR 3.2%
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- 49. Rivaroxaban Ongoing Clinical Trials DVT Einstein-DVT Rivarox15mg BID x 3 wks then 20mg Qday vs Enox/VKA PE Einstein-PE Rivarox 15mg BID x 3 wks then 20mg Qday vs Enox/VKA Medically Ill Rivarox 10mg Qday x 35 days vs Enox 40mg Qday x 10 days DVT/PE Einstein-Extension Rivarox 20mg Qday vs Placebo
- 50. Apixaban • Oral tablet •Bioavailability: 50% • Peak Plasma Levels = 3 hrs • Half-life ~ 12 hours • Metabolized in liver via CYP3A4 and CYP independent mechanisms • Eliminated via multiple pathways • No laboratory monitoring required • Has been submitted for approval by the US FDA
- 51. Apixaban Efficacy Outcomes inTKR 0 5 10 15 20 25 30 35 40 5 QDay 10 QDay 20 QDay Enox 30mg BID (n=152) Warf (n=153) 2.5 BID 5 BID 10 BID Apixaban (mg) (n = 933) Incidence of VTE and all-cause death (%) Duration = 10 -14 days Lassen MR, et al. J Thromb Haemost. 2007;5:2368 – 2375.
- 52. Apixaban Safety Outcomes inTKR 0 2 4 6 8 10 12 14 16 18 5 QDay 10 QDay 20 QDay Enox 30mg BID (n=152) 2.5 BID 5 BID 10 BID Apixaban (mg) (n = 933) Warf (n=153) Incidence of bleeding events (%)
- 53. 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
- 55. Ximelagatran • First target-specificoral 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
- 56. Dabigatran Etexilate • Potentand reversible oral Direct Thrombin Inhibitor • Inhibiting both clot bound and free thrombin • Predictable and consistent PK profile-Rapid onset/offset of action (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 CYP450 enzymes) 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
- 57. TRIALS IN PREVENTIONOF DVT • RE-MOBILISE • RE-NOVATE • RE-MODEL “Dabigatran was non inferior to enoxaparin in terms of efficacy and bleeding risks”
- 58. Dabigatran: Acute VTE Treatment RE-COVER AF and Stroke Prevention RE-LY SecondaryVTE Prevention RE-MEDY # Patients# Patients 25542554 1800018000 20042004 Study ArmsStudy Arms DabigatranDabigatran 150 mg BID150 mg BID vsvs warfarinwarfarin DabigatranDabigatran 100 mg BID100 mg BID and 150 mgand 150 mg BIDBID vsvs warfarinwarfarin DabigatranDabigatran 150 mg BID150 mg BID vsvs warfarinwarfarin
- 59. What about RE-LY? Dabigatranversus Warfarin in Patients with Atrial Fibrillation • Non-inferiority trial • Over 18,000 patients • Followup = 2 years Dabigatran 110 mg and 150mgDabigatran 110 mg and 150mg vs.vs. Adjusted dose warfarinAdjusted dose warfarin
- 60. Incidence of Strokeor Systemic Embolism RR 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, superiority Connolly SJ, et al. N Engl J Med. 2010;363:1875–1876. 183/6015 134/6076 202/6022 Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin 0.0 0.3 0.6 0.9 1.2 1.5 1.8 1.54 1.11 1.71 P<.001 (Sup) P<.001 (NI) RR 0.90 (95% CI: 0.74–1.10) RRR 35%
- 61. Events/n: BID, twice daily;RR, relative risk; RRR, relative risk reduction; Sup, superiority Connolly SJ et al. NEJM 2009; 361 (12): 1139-1151. 27/6015 36/6076 87/6022 Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin 0 0.6 0.9 Intracranialbleeding(%/yr) 0.8 0.7 0.5 0.4 0.3 0.2 0.1 0.23 0.30 0.74 RR 0.31 (95% CI: 0.20–0.47) P<.001 (Sup) RR 0.40 (95% CI: 0.27–0.60) P<.001 (Sup) RRR 69% RRR 60% Significantly Lower Intracranial Bleeding with Dabigatran
- 62. Most Common AdverseEvents Adverse event (%) Dabigatran 110 mg BID Dabigatran 150 mg BID Warfarin Dyspepsia* 11.8 11.3 5.8 Dyspnoea 9.3 9.5 9.7 Dizziness 8.1 8.3 9.4 Peripheral oedema 7.9 7.9 7.8 Fatigue 6.6 6.6 6.2 Cough 5.7 5.7 6.0 Chest pain 5.2 6.2 5.9 Arthralgia 4.5 5.5 5.7 Back pain 5.3 5.2 5.6 Nasopharyngitis 5.6 5.4 5.6 Diarrhoea 6.3 6.5 5.7 Urinary tract infection 4.5 4.8 5.6 Upper respiratory tract infection 4.8 4.7 5.2 Adverse events occurring in >5% of patients in any treatment group; *Occurred more commonly with dabigatran, P<.001;BID, twice daily Tablereproducedwithpermission:©2009MassachusettsMedicalSociety
- 63. PropertyProperty RivaroxabanRivaroxaban ApixabanApixabanIdraparinuxIdraparinux DabigatranDabigatran TargetTarget Factor XaFactor Xa Factor XaFactor Xa Factor XaFactor Xa (indirect)(indirect) ThrombinThrombin ROAROA OralOral OralOral SubcutaneousSubcutaneous OralOral ProdrugProdrug NoNo NoNo YesYes YesYes BioavailabilityBioavailability > 80%> 80% > 50%> 50% 100%100% 6%6% Time to peakTime to peak 33 33 ______ 22 Half-lifeHalf-life 9 hrs9 hrs 9 – 14 hrs9 – 14 hrs 80 hrs80 hrs 14 – 17 hrs14 – 17 hrs Frequency ofFrequency of AdministrationAdministration QdayQday BIDBID Q WeekQ Week Qday or BIDQday or BID DrugDrug InteractionsInteractions Potent CYP3A4 &Potent CYP3A4 & P-glycoproteinP-glycoprotein inhibitorsinhibitors Potent CYP3A4 &Potent CYP3A4 & P-glycoproteinP-glycoprotein inhibitorsinhibitors ______ P-glycoproteinP-glycoprotein inhibitorsinhibitors Renal excretionRenal excretion 66%66% 25%25% YesYes 80%80% Safe inSafe in pregnancypregnancy NoNo NoNo UnknownUnknown NoNo AntidoteAntidote NoNo NoNo NoNo NoNo Adapted from: Gross, PL. Arterioscler Thromb Vasc Biol. 2008; 28:380-386.
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- 65. PREVENTION OF DVT Principlesof treatment • HMWH • LMWH • Warfarin NEWER • Fondaparinux • Dabigatran 220 mg bd (Post THR, TKR) • Rivaroxaban 10 mg qd (Post THR, TKR) • In critically ill patients • Post THR, TKR • Orthopedic & other surgeries • Medical conditions like post MI, Stroke CONTEMPORARY
- 67. TREATMENT OF DVT Principlesof treatment • HMWH 80 U/kg STAT f/b 18 U/kg/hr infusion • LMWH NEWER • Fondaparinux • Dabigatran awaits approval by US FDA • Anti thrombotics- a must • Decision to be taken reg. IVC filters • 2nd VTE, unprovoked VTE & cancer associated VTE-indefinite duration • Else- 3-6 months duration CONTEMPORARY
- 68. TREATMENT OF PULMONARYEMBOLISM Principles of treatment • HMWH 80 U/kg stat f/b 18 U/kg/hr infusion • LMWH NEWER • Fondaparinux • Other trials are ongoing…. • Presence of RV dysfunction / hemodynamic instability Thrombolysis • Small to moderate PE- antithrombotics • Well’s criteria> 3- antithrombotics CONTEMPORARY
- 69. PREVENTION OF STROKEIN AF
- 70. Why do weneed long term anticoagulation ? • Atrial fibrillation (AF) is responsible for one-third of all strokes and 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 to non-valvular AF (NVAF) and valvular AF respectively • About one in four people at age 55 years will go on to develop AF (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 brain ischemia due to transient ischemic attacks and clinically ‘silent’ strokes, associated with Non valvular Atrial Fibrillation
- 71. PREVENTION OF STROKE INATRIAL FIBRILLATION • CLASS 1 INDICATIONS: 1.Presence of cardiac thrombus / DVT 2.In AF due to valvular causes 3.In AF due to non valvular causes (as per CHADS2 score)
- 72. Choice In AFdue to non valvular causes (as per CHADS2 score) • 1= aspirin / anticoagulant • >1=anticoagulant
- 73. PREVENTION OF STROKE Principlesof treatment • HMWH • LMWH NEWER • FONDAPARINUX • DABIGATRAN 110/150 mg BD • RIVAROXABAN 20 mg QD • APIXABAN awaits approval by US FDA • In AF • Mechanical heart valves • In cardiomyopathies • Inherited coagulopathies • DVT CONTEMPORARY
- 74. 150 mg OR110 mg DABIGATRAN ? 150 mg 110 mg < 75 years1, 2 ≥ 75 years1, 2 with risk factors: (i) Higher risk for bleed* (ii)Pharmacodynamic interactions** (iii)Factors increasing dabigatran plasma levels***1, 2 Superior vs warfarin for stroke1, 2 Noninferior vs warfarin for stroke1, 2 Noninferior vs warfarin for risk of major bleed1, 2 – Superior vs warfarin for ICH Superior vs warfarin for risk of major bleed1, 2 Superior 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 ophthalmic surgery, 8.Bacterial endocarditis **Acetylsalicylic acid, NSAID, Clopidogrel ***Moderate renal impairment (30-50ml/min CrCL), P- glycoprotein-inhibitor comedication
- 75. Prevention of AtrialFibrillation-Related Stroke
- 76. 76 The Newer Anticoagulantson the Horizon Trial Drug Dose Comparator N CHADS2 score RE-LY Dabigatran 150 mg and 110 mg* BID Warfarin (INR 2.0–3.0) 18,113 >0 ROCKET-AF5,6 Rivaroxaban 20 mg* OD Warfarin (INR 2.0–3.0) 14,264 ≥2 AVERROES3,4 Apixaban 5 mg BID Aspirin (81–324 mg OD) 6000 ≥1 ARISTOTLE1,2 Apixaban 5 mg BID Warfarin (INR 2.0–3.0) 18,201 ≥1 ENGAGE-AF TIMI 487 Edoxaban 30 mg OD 60 mg OD Warfarin (INR 2.0–3.0) >20,000 ≥2 *Adjusted based on renal function. BID, twice daily; INR, international normalised ratio; OD, once daily
- 77. PREVENTION OF STROKE INNON CARDIOEMBOLIC EVENTS “No evidence that warfarin is superior to aspirin 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
- 78. IN H.I.T Syndromes Withdrawheparin and initiate one of the following: •Lepirudin – preferred over Argatroban in hepatic diseases •Argatroban- preferred over lepirudin and fondaparinux in renal diseases •Fondaparinux “Warfarin NOT TO BE USED IMMEDIATELY post HMWH/LMWH”
- 79. Pre Cardiac catherisation(PCI) • LMWH / Bivaluridin preferred post MI
- 80. Potential Limitations ofNew Anticoagulants • 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)
- 81. FUTURE OF ANTICOAGULATION
- 82. Summary Dabigatran Rivaroxaban Apixaban Time to Marketfor New Anti-Thrombotic Agents 2010 2011 2012 2013 Otomaxiban
- 83. 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 Drugs TARGETED FACTOR Antithrombin (indirectly Xa and IIa) Antithrombin (indirectly Xa and IIa) Thrombin (IIa) Thrombin (IIa) Thrombin (IIa) Antithrombin Va, VIIIa Prothrombin (II), VII, IX, X Xa Xa Xa Xa Xa Xa Xa Xa Xa Thrombin (IIa) Thrombin (IIa)
- 84. • “HAD WARFARININTRODUCED INTO THE MARKET TODAY, THE US FDA WOULD HAVE REJECTED” -A FAMOUS CARDIOLOGIST DURING THE ESC “BUT STILL, WARFARIN REMAINS OUR POOR MAN’S CHOICE”
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Editor's Notes
- #4 NORMALLY THE ENDOTHELIUM HAS BOTH PRO AND ANTI THROMBOTIC PROPERTIES….IT SECRETES ANTIPLATELETS, ANTICOAGULANTS AD FIBRINOLYTICS AS WELL AS PLATELET AGGREGAMNTS, COAGULATION FACTORS, AND ANTIFIBRINOLYTIC AGNETS…..
- #8 We have 13 numbered coa. Factors along with HMWK and kallikreins…..
- #9 Explain the intrinsic and extrinsic pathways…
- #12 With these learned concepts in mind. Let us now venture into the topic proper-”anticoagualtion”…
- #13 An ideal anticoagulant ld prevent pathological thrombus formation, at the same time, preserve the body’s ability to respond to an endothelial injury….but the fact remains that, we still do not have a drug that has NO bleeding risk…all the drugs in our armamentarium have significant bleeding risks though the level of significance variesfrom one drug to the other….
- #14 Let us see which of our anticoagulants both contemporary and newer, who can come even close to these……
- #16 BUT IN THIS ERA OF EVIDENCE BASED MEDICINE, THE GUIDELINES HAVE BECOME A LOT SRINGENT AND WE NEED TO KNOW WHICH ANTICOAGULANT TO USE and WHEN AS PUT DOWN IN THE GUIDELINES which are formulated AFTER MANY META ANALYSES OF RCTs…..AND IN THIS PRESENTATION WE LL BE ADHERING TO THE LATEST GUIDELINES ISSUED BY THE CONCERNED AUTHORITIES….
- #17 The following at our disposal at present….
- #18 SO AS WE SEE HERE, WE DEFINITELY HAVE A BIGGER SPECTRUM OF ANTICOAGULANTS TO CHOOSE FROM...
- #19 LET US CLASSIFY THE…
- #20 AS WE HAVE SEEN PREVIOUSLY, THE BEST BET LD BE TO INHIBIT THIS MOECULE” THROMBIN”…..HMWH OR UFH HAS EQUAL THROMBIN INHIBITING AND FACTOR XA INHIBITING PROPERTIES….WHEREAS LMWH HAS LESSER OF THIS THROMBIN INHIBITION AND MORE OF FACTOR XA INHIBITION…WE LL SEE HOW….
- #21 AS WE HAVE SEEN PREVIOUSLY, THE BEST BET LD BE TO INHIBIT THIS MOLECULE” THROMBIN”…..HMWH OR UFH HAS EQUAL THROMBIN INHIBITING AND FACTOR XA INHIBITING PROPERTIES….WHEREAS LMWH HAS LESSER OF THIS THROMBIN INHIBITION AND MORE OF FACTOR XA INHIBITION…WE LL SEE HOW….
- #23 LET US CLASSIFY THE…
- #24 The following at our disposal at present….
- #26 The following at our disposal at present….THIS GROUP OF NEWER ORAL ANTICOAGULANTS HAS BEEN THE AREA OF INTENSE RESEARCH…..
- #28 KNOWING THIS IS IMPORTANT COS THESE DISADVANTAGES FORM THE BASIS FOR THE CONTINUOUS SEARCH OF THE NEWER ANITCOAGULANTS…
- #31 Long chain inclues the high affinity pentasaccharaide sequence…
- #32 WITH THESE BASICS, LETS SEE THE SIDE EFFECTS OF UNFARCTIONATED HEPARIN AND SEE GHOW LMWH SCORES BETTER THAN IT….
- #34 Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity.
- #40 The indications and where each of these anitcoagualnts are approved to use will be dealt shortly….
- #41 Was a very atrractive option when introduced, but, Failed to prove superiorty over LMHW and bleeding risks were higher….
- #44 Potent selective inhibitor of factor Xa. Absorption: well absorbed from GI tract with Bioavail > 80% The terminal t1/2 is ~ 5-9 hrs in young individual and 11-13 hrs in the elderly Dual mechanism of excretion. 66% in the kidneys and the remainder in the feces 30-40% excreted unchanged in the urine and excreted via a combination of glomerular filtration and tubular secretion and the remainder reflects metabolites. Use in caution for pts with renal insufficiency. Intestinal excretion of rivaroxaban appears to be mediated, by P-glyp (transport protein) The drug is contraindicated in pts with severe liver dx b/c of metabolic inactivation may be impaired. Also caution should be used in patients receiving tratment with potent inhibitors of both CYP3A$ and P-glyp (ketoconazole/ritonovir) Reduced fecal and renal clearance of rivaroxaban by these drugs can cause exaggerated anticoagulant effect Rivaroxaban prolongs the PT and aPTT, with the PT being more sensitive than the aPTT depending on the reagents used for testing. The effect of the drug on these tests is short-lived with prolongation only seen at peak drug levels. Factor Xa inhibition is the best test to monitor drug concentrations in plasma.
- #45 Regulation of Coagulation in major Orthopedic surgery reducing the Risk of DVT and PE (RECORD) RECORD 1 and 2: THR surgery RECORD1: Rivaroxaban 10mg once daily (Primary endpoint: 1.1% vs. 3.7%; p <0.001 Major bleeds: 0.3% vs 0.1%) -RECORD2: Rivaroxaban 10 mg once daily (Primary enpoint: 2.0% vs 9.3%; p<0.001 Major bleeds: 0.1% vs. 0.1%) Results showed an impressive 50% reduction in DVT, nonfatal PE, and all-cause mortality favoring the once daily rivaroxaban treated group over enoxaparin. Also an equally impressive 60% statistically significant risk reduction, again favoring rivaroxaban over enoxaparin for major VTE. Appeared to be no differences in major bleeding or any severity of bleeding between groups.
- #46 Rivaroxaban 10mg once daily vs. FDA approved Enoxaparin 30 mg SC BID RRR of 31% in primary endpoint (reduction in total VTE events) for rivaroxaban (6.9% vs. 10.1% p = 0.012) There was a trend towards more major bleeding events with rivaroxaban compared with enox, despite use of a 50% higher dose of enoxaparin than in RECORD 1,2, or 3 but the difference was not statistically significant (0.7% vs. 0.3%; P> 0.05)
- #50 EINSTEIN DVT and PE (Phase II) EINSTEIN Extension: focused on once daily dosing Other studies: ODIXa – HIP (Phase II) vs. Enox ODIXa – HIP2 (Phase II) vs. Enox ODIXa – Knee (Phase II) vs. Enox ODIXa – OD – HIP (Phase II) vs. Enox - ODIXa-DVT (Phase II) vs. Enox and warfarin
- #51 Absorption: Bioavailability = 50% - 81% Peak Plasma levels = 3 hrs t ½ = 9-14 hrs = Long – especially in the elderly may be prolonged Metabolized: in the liver via CYP3A4 and CYP independent mechanisms Excretion: Dual mechanism – 25% kidneys / 75% = biliary/feces Monitoring: using a factor Xa inhibition assay or a dilute prothrombin time **Apixiban prolongs PTT and INR in a concentration-dependent fashion – however effect on these tests is minimal at therapeutic concentrations. - Followup drug to Razaxaban (halted due to high bleeding) = similar characteristics
- #52 N (TOTAL) = 1238 Phase II Double Blind Randomized study of 1238 pts undergoing TKR. Apixaban 1/6 doses, open label warfarin, or enoxaparin 30 mg BID Followup at day 42 The composite of VTE and mortality were lower with all apixaban doses vs. enoxaparin and warfarin, although apixaban dose-dependency did not achieve significance P = 0.09) When looking at the overall riskk-benefit profile, apixaban 2.5mg twice daily or 5mg once daily appeared the most promising dose regimen for further phase three considerations.
- #53 Bleeding Rates were significantly dose-dependent with the once (P= 0.01) and twice daily (P=0.02) apixaban regimens
- #54 So when we have a superior ORAL drug with the the safety profile as a parenteral drug, then why not go for it !!!
- #57 The main advantages over present strategies are highlighted in bold italics.
- #59 REVOLUTION TRIAL PROGRAM = phase 3 program that will be enrolling over 27,000 patients worldwide and includes REMODEl, REMOBILIZE, and RENOVATE studies in primary VTE prevention in ortho patients REMOBILIZE: Dabigatran with enoxaparin dose 30mg BID started post-procedurally in pts undergoing TKA. The 150mg and 22mg daily dose did not meet the non-inferiority design compared with enoxaparin. OTHER STUDIES RESOLVE, RECOVER, REMEDY = VTE treatment and secondary thromboprophylaxis RELY - Dabigatran 110 mg = similar rates of stroke and systemic embolization and lower rates of major hemorrhage Dabigatran 150 mg = lower rates of stroke and systemic embolism but with similar rate of major hemorrhage **Rate of MI was higher with both doses of dabigatran than with warfarin** **Did not find liver toxicity with dabigatran in RE-LY pts**
- #60 Dabigatran 110 mg = similar rates of stroke and systemic embolization and lower rates of major hemorrhage Dabigatran 150 mg = lower rates of stroke and systemic embolism but with similar rate of major hemorrhage **Rate of MI was higher with both doses of dabigatran than with warfarin**
- #61 Rates of the primary outcome were 1.69% per year in the warfarin group, as compared with 1.53% per year in the group that received 110 mg of dabigatran (relative risk with dabigatran, 0.91; 95% confidence interval [CI], 0.74 to 1.11; P<0.001 for noninferiority) and 1.11% per year in the group that received 150 mg of dabigatran (relative risk, 0.66; 95% CI, 0.53 to 0.82; P<0.001 for superiority). There was a definite advantage of the 150 mg group in terms of superiority over warfarin
- #62 Warfarin was associated with less ICH vs fixed dose warfarin + ASA or dual antiplatelet treatment. Here in RELY, there is a significant reduction even beyond that. This is significant for clinical practice in that fear of ICH should now be a minimal concern when taken in balance with stroke prevention.
- #63 Note to speaker: The dyspepsia incidence is dealt with later on as an FAQ. Table reproduced with permission: Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009;361:1139–51 Copyright ©2009 Massachusetts Medical Society. All rights reserved
- #65 THIS IS VERY IMPORTANT FOR A PHYSICAIN TO KNOW WHAT TO DO WHEN?
- #66 Well’s criteria-
- #68 Well’s criteria-
- #69 Well’s criteria -prior dvt /pe, hr, immobilisation, cancer, hemoptysis, dvt….based on RECOVER trials….
- #71 Published trials in order of year of major publication. ACTIVE-W Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events; AFASAK Atrial Fibrillation, ASpirin, AntiKoagulation; ATAFS Antithrombotic Therapy in Atrial Fibrillation Study; BAATAF Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA Canadian Atrial Fibrillation Anticoagulation; EAFT European Atrial Fibrillation Trial; ESPS European Stroke Prevention Study; FFAACS Fluindione Fibrillation Auriculaire Aspirin et Contraste Spontane´; JAST Japan Atrial fibrillation Stroke Trial; JNAFESP Japanese Nonvalvular Atrial Fibrillation Embolism Secondary Prevention; LASAF Low-dose Aspirin, Stroke, Atrial Fibrillation; MWNAF Minidose Warfarin in Nonrheumatic Atrial Fibrillation; NASPEAF NAtional Study for Prevention of Embolism in Atrial Fibrillation; PATAF Prevention of Arterial Thromboembolism in Atrial Fibrillation; PETRO Prevention of Embolic and ThROmbotic events; SAFT Swedish Atrial Fibrillation Trial; SIFA Studio Italiano Fibrillazione Atriale; SPAF Stroke Prevention in Atrial Fibrillation; SPINAF Stroke Prevention in Nonrheumatic Atrial Fibrillation; SPORTIF Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation; UK-TIA United Kingdom Transient Ischaemic Attack; WASPO Warfarin vs. Aspirin for Stroke Prevention in Octogenarians.
- #75 The decision to test two doses of dabigatran in a large phase II trial was taken because the identification of the correct dose was considered critical to ensure the optimum balance of efficacy and safety. The 150 mg bid dose had been tested in the phase II PETRO study, whereas 110 mg bid had not been directly tested. The choice of this lower dose was based on interpolations of phase II data, considering the time course and the peak of the anticoagulant effect of dabigatran, and on the observation that a total daily dose of 220 mg was effective for the prevention of deep-vein thrombosis in patients undergoing orthopedic surgery. The two-dose approach used in RE‑LY ® may also allow the opportunity to tailor dabigatran dosing to individual patient characteristics in order to maximize the benefit/risk ratio.
- #77 Only dabigatran is presently approved for SPAF in the following countries: Canada, Colombia, Israel, Namibia, New Zealand, Philippines, USA, Japan, Australia, Indonesia, Singapore, Korea, Malaysia. References: NCT00412984. www.clinicalTrials.gov. Accessed September 9, 2010. Lopes RD, et al. Am Heart J. 2010;159:331-339. NCT00496769. www.clinicalTrials.gov. Accessed September 9, 2010. Eikelboom JW, et al. Am Heart J. 2010;159:348-533. NCT00403767. www.clinicalTrials.gov. Accessed September 9, 2010. ROCKET-AF Study Investigators. Am Heart J. 2010;159:340-477. NCT00781391. www.ClinicalTrials.gov. Accessed September 9, 2010.
- #79 Cos in HIT protein c and s is also consumed keading to their deficiency…
- #80 PCI has been the standard of acre now a days…..need to perform PCI at the earliest need not be overemphasised now….spo inorder to faciolitate…
- #81 Antidote : SSR 126517 (Factor Xa Inhibitor) is the only new anticoagulant being studied that has an antidote. Neutralization of Direct Factor Xa Inhibitors: plasma derived or recombinant factor Xa modified to lack catalytic and membrane binding activities, can neutralize the effects of small molecular factor Xa and LMWH Dialysis is likely to clear the direct factor Xa or Thrombin inhibitors = all of which are small molecules