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Oral anticoagulants ppt

dr shalini garg
dm cardiology

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Oral anticoagulants ppt

  2. 2. HEMOSTATIC SYSTEM In Brief…….
  3. 3. WHEN DOES BLOOD COAGULATE ?  Injury to blood vessel. eg: Plaque rupure  Blood stasis. eg: AF  Procoagulants > Anticoagulants. eg: Coagulation disorders
  6. 6. Figure. Classification of established anticoagulants and new anticoagulants that were recently licensed for use or are in advanced stages of clinical development. fIXa indicates factor IXa. *Indirectly inhibit coagulation by interacting with antithrombin. †AVE5026 is an ultralow-molecular-weight heparin that primarily inhibits fXa and has minimal activity against thrombin. Eikelboom J W , and Weitz J I Circulation. 2010;121:1523- 1532 Copyright © American Heart Association, Inc. All rights reserved.
  7. 7. CLASSIFICATION OF ORAL ANTICOAGULANTS Coumarin Derivatives e.g. Warfarin, Acenocoumarol (Acitrom) Indandione Derivatives e.g. Phenindione, Anisindione Newer anticoagulants  Direct thrombin inhibitors Dabigatran etexilate (Pradaxa)  Direct factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban Edoxaban (DU-176b) Betrixaban
  8. 8. WARFARIN almost 70 years old and still causing problems… Still we have to stick with it…
  9. 9. HISTORY  In the 1920s cattle in the Northern USA and Canada were afflicted by an outbreak of an unusual disease characterized by fatal bleeding, either spontaneously or from minor injuries. Mouldy silage made from sweet clover ( Melilotus alba and M. officinalis ) was implicated, and L M Roderick in North Dakota showed that it contained a haemorrhagic factor that reduced the activity of prothrombin.  However, it was not until 1940 that Karl Link and his student Harold Campbell in Wisconsin discovered that the anticoagulant in sweet clover was 3,3′methylenebis (4-hydroxy coumarin). Further work by Link led in 1948 to the synthesis of warfarin, which was initially approved as a rodenticide in the USA in 1952, and then for human use in 1954.  The name warfarin is derived from WARF (Wisconsin Alumni Research Foundation) and –arin from coumarin.
  10. 10. WARFARIN  Most widely used anticoagulant in the world  Coumarin derivative, water soluble vit K antagonist  Low cost and highly effective, if given in right way.
  11. 11. Vitamin K-dependent clotting factors (FII, FVII, FIX, FX, Protein C/S/Z) Epoxide Reductase  -Carboxylase (GGCX) MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle Warfarin Inactivation CYP2C9 Pharmacokinetic Post translational modification
  12. 12. PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS Factor II 72h Factor VII 6h Factor IX 24h Factor X 36h Peak anticoagulant effect may be delayed by 72 to 96 hours
  13. 13. PHARMACOLOGY  Recemic micture of R and S isomers (S more active)  Rapidly and completely absorbed from GI tract  Blood level peaks about 90 min of administration  90% of circulating warfarin is bound to albumin  Plasma t1/2 is 36-42 hrs  Only small fraction of unbound warfarin is biologically active  Warfarin is accumulates in liver, where it undergoes CYP2C9 mediated oxidative metabolism.  Inactive metabolites are excreted in urine and stools.
  14. 14. • CYP2C9 SNPs alter warfarin metabolism:  CYP2C9*1 (WT) – normal activity  CYP2C9*2 (Arg144Cys) - low/intermediate activity  CYP2C9*3 (Ile359Leu) - low activity • Two relatively common variants, CYP2C9*2 and CYP2C9*3, encode an enzyme with reduced activity. requiring lower maintenance doses of warfarin. • Approximately 25% of whites have at least one variant allele of CYP2C9*2 or CYP2C9*3, whereas these variant alleles are less common in blacks and Asians • Warfarin dose reduction requires as follow: • Heterozygosity for CYP2C9*2 or CYP2C9*3 allele : 20%-30% • Homozygosity for the CYP2C9*2 or CYP2C9*3 allele : 50%-70% Effect of CYP2C9 Genotype on Anticoagulation
  15. 15. Effect of CYP2C9 Genotype on Anticoagulation-Related Outcomes (Higashi et al., JAMA 2002) N 127 28 4 18 3 5
  16. 16. VKORC1: New Target Protein for Warfarin Epoxide Reductase  -Carboxylase (GGCX) Clotting Factors (FII, FVII, FIX, FX, Protein C/S/Z) Rost et al. & Li, et al., Nature (2004) (VKORC1) 5 kb - chr 16
  17. 17. Effect of VKORC1 Genotype on Anticoagulation  Three polymorphic variants of VKORC1  Non-A,Non-A : wild type – Requiring more warfarin dose  Non-A/A : Heterozygous – Requiring 25% dose reduction  A/A : Homozygous - Requiring 50% dose reduction  Means wild type having more resistance to warfarin while homozygous is more sensitive.  Asians have the highest prevalence of VKORC1 variants, followed by whites and blacks  Polymorphisms in VKORC1 likely explain 30% of the variability in warfarin dose requirements.  VKORC1 variants are more prevalent than variants of CYP2C9 Genotype Freq in Asians (%) Dose reduction Non-A,Non-A : wild type 7 -- Non-A/A : Heterozygous 30 26 A/A : Homozygous 63 50
  18. 18. These findings prompted the U.S. Food and Drug Administration (FDA) to amend the prescribing information for warfarin to indicate that lower initiation doses should be considered for patients with CYP2C9 and VKORC1 genetic variants.
  19. 19. DOSING  Usual dose is 5 mg/day (1-20 mg)  Lower doses require in  Elderly  Pt on increased risk of bleeding eg. Pt on aspirin  Heart failure  Liver disease  Renal impairment  Malnutrition  Thyrotoxicosis (Opposite in Myxedema)  Asian patients: Explained by genetic variation in hepatic enzymes (CYP3C9 & VKORC1 Polymorphism)  High intake dietary Vit-K (green vegetables e.g. broccoli) reduces the efficacy of Warfarin.  Practically best time to give warfarin is ~ 6 PM.
  20. 20. Caution with VITAMIN K containing food Health Canada recommends a daily intake of 90 – 120 micrograms (μg) of vitamin K. The total amount of vitamin K from day to day may be higher or lower than the recommended amount. It is okay to eat food with different levels of vitamin K, but because vitamin K can interfere with blood-thinning effects of warfarin, it is important to eat the same amount from day to day. Do not eat a lot one day and none the next
  21. 21. Why to add concomitant parenteral anticoagulation ?  Because of delayed onset of action, concomitant parenteral anticoagulant should be given in pts with established thrombosis or high risk for thrombosis until INR has been in therapeutic range for at least 2 days.  Warfarin monotherapy decreases the levels of two endogenous anticoagulants, proteins C and S, thus increasing thrombogenic potential. Overlapping warfarin for at least 5 days with an immediately effective parenteral anticoagulant counteracts the procoagulant effect of unopposed warfarin.  Usually a minimum 5 days of concomitant parenteral anticoagulation is recommended.
  22. 22. Commencement of oral anticoagulant therapy If the baseline INR≤1.3 the patient will receive 5mg of warfarin once daily on days 1 and 2. The INR is checked on day 3 and 4 and the warfarin dose is adjusted according to the schedule.
  23. 23. Monitoring  B/z of narrow therapeutic window of warfarin  Standard procedure is to check the PT-INR as follows: INR daily until it is in therapeutic range 3 times weekly for 2 weeks Once stable & warfarin dose is known INR every 3-4 weeks or more frequently if introduction of any new medications
  24. 24. What is PT-INR  Warfarin therapy is most often monitored using the prothrombin time, a test sensitive to reductions in the levels of prothrombin, factor VII, and factor X.  This test involved addition of thromboplastin (a reagent containing TF, phospholipid & Ca++) to citrated plasma and determining the time to clot formation.  Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors  INR represent the PT according to international reference thromboplastin, as approved by WHO.
  25. 25. INTERNATIONAL NORMALISED RATIO (INR) INR = [PTpt] ISI [PTRef] PTpt – prothrombin time of patient PTRef – prothrombin time of normal pooled sample ISI – International Sensitivity Index  Highly sensitive thromboplastins have an ISI of 1.0  Most current thromboplastins have ISI values that range from 1.0 to 1.4
  26. 26. Indications  Atrial fibrillation  Prosthetic heart valve  Venous thromboembolism  Primary pulmonary hypertension  Rarely after Acute MI (If associated with high risk of thromboembolism e.g. AF, mobile or pedunculated mural thrombus or prior venous thromboembolism)
  27. 27. Warfarin in AF CLASS I For patients with nonvalvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater, oral anticoagulants are recommended. Options include: warfarin (INR 2.0 to 3.0) (Level of Evidence: A), dabigatran (Level of Evidence: B), rivaroxaban (Level of Evidence: B), or apixaban (Level of Evidence: B)
  28. 28. Heart valve prostheses The risk of systemic embolism from prosthetic heart valves depends on the type of valve, its position and other factors that contribute to the patients’ risk of developing thrombosis, such as cardiac rhythm and dilatation.
  29. 29. Warfarin in Venous thromboembolism  Warfarin should be initated concurrently with parenteral heparin.  For VTE patients, the usual target INR range is between 2.0 and 3.0.  After 5 days, warfarin alone should be continued for at least 3 months  Optimal duration of anticoagulation depends on clinical settings
  30. 30. Optimal duration of anticoagulation CLINICAL SETTING RECOMMENDATION 1st provoked PE/proximal leg DVT 3 to 6 months 1st provoked upper extremity DVT or isolated calf DVT 3 months 2nd provoked VTE Uncertain 3rd VTE Indefinite duration Cancer and VTE Consider indefinite duration or until cancer is resolved Unprovoked PE/proximal leg DVT Consider indefinite duration 1st unprovoked calf DVT 3 months 2nd unprovoked calf DVT Uncertain
  31. 31. WARFARIN IN STEMI 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: Class I 1. Anticoagulant therapy with a vitamin K antagonist should be provided to patients with STEMI and AF with CHADS2 score greater than or equal to 2, mechanical heart valves, venous thromboembolism, or hypercoagulable disorder. (Level of Evidence: C) 2. The duration of triple antithrombotic therapy with a vitamin K antagonist, aspirin, and a P2Y12 receptor inhibitor should be minimized to the extent possible to limit the risk of bleeding. (Level of Evidence: C)
  32. 32. Class IIa 1. Anticoagulant therapy with a vitamin K antagonist is reasonable for patients with STEMI and asymptomatic LV mural thrombi. (Level of Evidence: C) Duration of treatment is 3 months. Class IIb 1. Anticoagulant therapy may be considered for patients with STEMI and anterior apical akinesis or dyskinesis. (Level of Evidence: C) 2. Targeting vitamin K antagonist therapy to a lower international normalized ratio (eg, 2.0 to 2.5) might be considered in patients with STEMI who are receiving DAPT. (Level of Evidence: C)
  33. 33. Side effects of Warfarin  Bleeding  Skin necrosis  Purple toe syndrome  Teratogenicity  Osteoporosis  Others: Agranulocytosis, leukopenia, diarrhoea, nausea, anorexia.
  34. 34. Bleeding  Most common complication  In form of  Mild: epistaxis, hematuria  Severe: Retroperotoneal or gastrointestinal bleeding  Life-threatening : Intracranial bleed  Rate of major bleeding (defined as any visit to hospital for hemorrhage) is 1- 3% per person-year  Half of the complications occurs because INR exceeds therapeutic range  Can be minimized by keeping INR in therapeutic range
  35. 35. Interventions according to INR/symptoms Asymptomatic pts with raised INR INR INTERVENTION 3.5 - 4.5 Withhold warfarin until in therapeutic range Decrease the dose of warfarin > 4.5 Low dose sublingual/oral Vit K (not routinely) 4.5 – 9.0 Vit k 1 mg > 9.0 Vit k 2-3 mg Higher doses of vitamin K (up to 10 mg) can be administered if more rapid reversal of the INR is required Although vitamin K administration results in a more rapid reduction in the INR, there is no evidence that it reduces the risk of hemorrhage
  36. 36. Symptomatic pts with raised INR SYMPTOMS INTERVENTION Mild bleeding Withhold warfarin Severe bleeding Vit k 10 mg slow i/v infusion ± FFP (15 ml/kg) Life threatening bleeding or pt can’t tolerate volume overload Prothrombin complex concentrate (II,IX & X) Prosthetic valves pts Vit K should be strictly avoided, unless there is life threatening intracranial bleed (Valve thrombosis) Subcutaneous Vit K gives variable results and should be avoided
  37. 37. SKIN NECROSIS  Rare but very serious complication of warfarin (prevalence of 0.01-0.1 %)  Occurs 2 to 5 days after initiation of warfarin  Usually occurs after high dose of warfarin  Typical presentation is : Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. Typically, the center of the lesion becomes progressively necrotic. Examination of skin biopsies taken from the borders of these lesions reveals thrombi in the microvasculature
  38. 38. Warfarin (Coumadin)–induced skin necrosis on the lower abdomen & breast
  39. 39.  Mechanism : Not well understood but a precipitous fall in plasma protein C or S levels (natural anticoagulants) before warfarin exert anticoagulant effect, results in procoagulant state triggering thrombosis of adipose tissue microvasculatures.  Treatment :  Discontinuation of warfarin and reversal with vitamin K, if needed  An alternative anticoagulant, such as heparin or LMWH, should be given to patients with thrombosis  Protein C concentrates or recombinant activated protein C may accelerate healing of the skin lesions in protein C deficient patients  Frozen plasma may be useful for those with protein S deficiency  Occasionally, skin grafting is necessary when there is extensive skin loss.  Prevention :  Start with low dose warfarin in pts with known Protein C or S deficiency  Overlapping with a parenteral anticoagulant when initiating warfarin therapy
  40. 40. Purple toes syndrome  Extremely uncommon cutaneous complication  Characterized by the sudden appearance of bilateral, painful, purple nonhemorrhagic lesions on the toes and sides of the feet that blanch with pressure  Usually develops 3-8 weeks after the start of warfarin therapy  Mechanism: release of atheromatous plaque emboli  Discontinue COUMADIN therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary. Pharmacotherapy. 2003 May;23(5):674-7
  41. 41. Teratogenicity  Occurs in 3.5 – 6 %  Depends on time of gestation and dose of warfarin given  Usually in first trimester of pregnancy  It causes characteristic embryopathy consist of :  Nasal hypoplasia and  Chondrodysplasia punctata (epiphyseal and vertebral bone  stippling)  Cleft lip and (or) palate  Choanal stenosis/atresia  Central nervous system abnormalities  Coarctation of aorta (Rare malformations described following first trimester exposure to warfarin)  Occurs especially if warfarin dose is > 5 mg/day
  42. 42. Lateral view X-ray showing calcifications and irregular ossification of lumbar and sacral vertebrae, consistent with warfarin embryopathy
  43. 43. OSTEOPOROSIS  Long- term use of warfarin (> 1 yr)  More common in males  60% increased risk of osteoporosis-related fracture in men  Mechanism: combination of reduced intake of vitamin K, which is necessary for bone health, and inhibition by warfarin of vitamin K-mediated carboxylation of certain bone proteins, rendering them nonfunctional  Beta-adrenergic antagonists may protect against osteoporotic fractures
  44. 44. Warfarin in special conditions…
  45. 45. Pregnancy  It causes…  Fetal abnormalities (Teratogenic)- in first trimister  Chances of intracranial bleeding in baby while passage through birth canal – in third trimister  Because of this, warfarin is contraindicated in 1st (first 12 weeks) & 3rd trimsters (last 2 weeks)  Warfarin does not passes in breast milk & is safe for nursing mothers.
  46. 46. Warfarin modification before surgery  Pt on long term anticoagulation with warfarin should stop it 5 days in prior to elective surgery to allow INR to return to normal level  Those at high risk of thromboembolism can be bridged with once or twice daily s/c LMWH once the INR fall below 2. For pragmatic purposes, to save monitoring the INR as an out-patient, bridging therapy can be instituted with therapeutic dose LMWH 2-3 days after warfarin is stopped i.e. on the morning after two doses have been omitted.  The last dose of LMWH should be given 12 or 24 hrs before depending on bd or od dose respectively
  47. 47.  In patients who are receiving bridging anticoagulation with therapeutic dose UFH, the heparin should be stopped 4 - 6 hours before surgery.  If possible the INR should be determined the day before surgery. This allows the administration of oral vitamin K (2 or 2.5 mg) if the INR is ≥ 1.5 so reducing the risk of cancellation.  The INR should be checked on the day of surgery.  Heparin should be resumed approximately 24 hours after the procedure if there is adequate haemostasis but should not be started until at least 48 hours after surgery in high bleeding risk surgeries  Warfarin can be resumed, at the normal maintenance dose, the evening of surgery or the next morning if there is adequate haemostasis.
  48. 48. Dentistry in anticoagulated patients The risk of significant bleeding in patients on oral anticoagulants and with an INR of ≤ 4.0 is small and the risk of thrombosis may be increased in patients in whom oral anticoagulants are temporarily discontinued. Oral anticoagulants should not be discontinued in the majority of patients requiring out-patient dental surgery including dental extraction. The risk of bleeding may be minimised by: The use of oxidised cellulose (Surgicel) or collagen sponges and sutures. 5% tranexamic acid mouthwashes can be used four times a day for 2 days . For patients stably anticoagulated on warfarin, a check INR is recommended 72 hours prior to dental surgery. Patients on warfarin should not be prescribed NSAIDs as analgesia following dental surgery.
  49. 49. Endoscopy in anticoagulated patients In general, low risk diagnostic procedures including mucosal biopsy can be performed when the INR is up to 2.5, without altering anticoagulation. For therapeutic procedures the risk of post-procedure bleeding is higher and it is better to adjust anticoagulation.
  50. 50. ACENOCOUMAROL (acitrom)  Same as warfarin with following differences:  Shorter half life 10-16 hrs  More rapid onset of action on PT  Shorter duration of action (2 days)  Causes GI disturbances, oral ulcerations and dermatitis  4 mg on day one, 4-8 mg on the day 2nd then maintenance dose 1-8 mg according to response by PT test
  51. 51. THE OVERALL ANTICOAGULATION QUALITY IS SIGNIFICANTLY BETTER WITH WARFARIN AS COMPARED TO ACENOCOUMAROL 72% 67% 64% 66% 68% 70% 72% %Responders Warfarin Acenocoumarol Thrombosis And Haemostasis 1994; 71(2): 188-191
  52. 52. Newer Oral Anticoagulants
  53. 53. Why we need alternatives to warfarin ???
  54. 54. What’s wrong with warfarin? 1. Narrow therapeutic range 2. Slow onset of action 3. Slow offset of action (long duration of action, long elimination half life) 4. Multiple drug and dietary interactions 5. Monitoring required to maintain in therapeutic range 6. Difficult to manage for invasive procedures 7. Under-use of therapy due to fear of adverse events and complexity of management
  55. 55. 8. Efficacy is dependent upon infrastructure Time in therapeutic range (TTR) is associated with improved safety and efficacy TTR is greater in countries with more sophisticated health care infrastructure.
  56. 56. What are the attributes of the ideal anticoagulant? 1. Oral administration 2. Rapid onset of action/rapid offset of action 3. Wide therapeutic range 4. Predictable therapeutic effect with fixed or weight-based dosing 5. No food or drug-drug interactions 6. No monitoring required (but the ability to monitor if desired) 7. Well defined pharmacokinetics in presence of renal or hepatic disease 8. Easily reversible 9. Cost effective
  57. 57. Newer oral anticoagulants
  58. 58. Classification  Direct thrombin (IIa) inhibitor  Dabigatran (Pradaxa)  Factor Xa inhibitors  Rivaroxaban (Xarelto)  Apixaban
  59. 59. Dabigatran etexilate (Pradaxa)  Oral Direct thrombin (factor IIa) inhibitor  It is a prodrug & does not exhibit any pharmacological activity  Initially recommended by FDA on October 19, 2010 for Non-valvular AF
  60. 60. Mechanism of Action Dabigatran and its acyl glucuronides are competitive, direct thrombin inhibitors. Both free and clot-bound thrombin, and thrombin-induced platelet aggregation are inhibited by the active moieties.
  61. 61. Pharmacokinetics Dabigatran etexilate mesylate is absorbed as the dabigatran etexilate ester. The ester is then hydrolyzed, forming dabigatran, the active moiety. The t1/2 is 15 to 17 hrs. 90% is excreted unchanged in urine. Absorption The absolute bioavailability of dabigatran following oral administration of dabigatran etexilate is approximately 3 to 7% . Cmax occurs at 1 hour post-administration in the fasted state. Coadministration of PRADAXA with a high-fat meal delays the time to Cmax by approximately 2 hours but has no effect on the bioavailability of dabigatran; PRADAXA may be administered with or without food.
  62. 62.  Minimal metabolism of dabigatran by CYP3A4 enzymes is clinically insignificant  No dose modification required in hepatic impairment  Dabigatran is also a substrate for P- glycoprotein ( a trans-membrane pump expelling drugs out of cell). So P- glycoprotein inhibitors (e.g. amiodarone, verapamil & clarithromycin) can increase whereas inducers (e.g. rifampicin, st. john’s wart) may reduce dabigatran level in plasma.
  63. 63. Pharmacodynamics Dabigatran prolongs aptt which targets intrinsic pathway of coagulation; thrombin clotting time (TT), which directly assesses the activity of thrombin in a plasma sample; and the ecarin clotting time, which is a specific assay for thrombin generation. However, at clinically relevant plasma concentrations, dabigatran has relatively little effect on the prothrombin time and INR, which targets the extrinsic coagulation pathway. The TT assay is the most sensitive to prolongation by dabigatran, followed by the ecarin clotting time and aPTT.
  64. 64.  The relationship between plasma concentrations of dabigatran and the TT, and ecarin clotting time is linear (ie, dabigatran prolongs the TT, and ecarin clotting time in a concentration dependent fashion over therapeutic concentrations), whereas the aPTT concentration-response curve is curvilinear and flattens at higher concentrations (200 ng/mL).
  65. 65. A dilute thrombin time assay (Hemoclot test, Hyphen Biomed, France) has been certified in Europe since late 2010 for the quantitative determination of dabigatran plasma levels. It can be calibrated with dabigatran standards.
  66. 66. INDICATIONS AND USAGE  Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation  Treatment of Deep Venous Thrombosis and Pulmonary Embolism Pradaxa is indicated for the treatment of deep venous thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5-10 days.  Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
  67. 67. Recommended dose
  69. 69. If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.
  70. 70. Dabigatran hydrolyze over time when exposed to humidity, causing a breakdown of active ingredient, and rendering the medication less effective
  71. 71. Converting pts from or to Warfarin  From warfarin to dabigatran  Stop warfarin & start dabigatran once INR fall below 2  From dabigatran to warfarin  Adjust the starting time of warfarin based on creatinine clearance CrCL (ml/min) Days before stopping dabigatran > 50 3 days 50 - 30 2 days 30 - 15 1 day < 15 or dialysis not recommended
  72. 72. Converting pts from or to parenteral anticoagulants From parenteral anticoagulants to dabigatran  Intermittent parenteral anticoagulant  Start dabigatran 0-2 hrs before next dose  Continuous parenteral anticoagulant (e.g. UFH)  Start dabigatran at the time of stopping parenteral anticoagulant  From dabigatran to parenteral anticoagulants  Wait for 12 hrs (CrCl> 30 ml/min) or 24 hrs (CrCl< 30 ml/min) after last dose of dabigatran before starting parenteral anticoagulant
  73. 73. Dabigatran in pts planned for elective surgery  If possible, stop dabigatran 1-2 days before (CrCl> 50 ml/min) or 3-5 days before (CrCl< 50 ml/min) invasive or surgical procedures.  Longer periods may be considered if pt undergoing 1. Major surgery 2. Spinal puncture 3. Placement of spinal or epidural catheter or port
  74. 74. Dabigatran in pts planned for emergency surgery  Because specific antidote is not available, options are  Either have to wait until the anticoagulant effect has spontaneously diminished Or  Undergo their procedure with the knowledge that they have a increased risk of bleeding
  75. 75. Postoperative management  It depends almost exclusively on the postoperative risk of bleeding  Procedures with with good hemostasis shortly after the end of the procedure, resumption on same evening can be done (i.e. minimum of 4 to 6 hours after surgery) starting with a half dose (75 mg) for the first dose, and thereafter the usual maintenance dose.  For major abdominal surgery or urologic surgery with incomplete hemostasis, resumption should be delayed until there is no drainage or other evidence of active bleeding
  77. 77. Monitoring anticoagulant effect of dabigatran  Need not to assess regularly (ex. In the setting of emergency surgery)  In emergency most accessible tests are 1. TCT 2. aPTT  If the TCT is normal, it is safe to assume that the level of dabigatran is very low and that the patient’s risk of bleeding development is similar to that of other patients undergoing the procedure
  78. 78. Antidote  Specific agent not available  Though limited data, following agents may be used  Activated prothrombin complex concentrate  Recombinant factor VIIa  Concentrate of coagulant factors II, IX and X  Hemodialysis (because only 35% of dabigatran is bound to plasma proteins) Protamine sulfate and Vit-K are not helpful
  79. 79. Adverse effects  Bleeding – increases with age  GI events  Dyspepsia (12%)  Abdominal pain  Gastritis including GERD, esophagitis, erosive gastritis, gastric hemorrhage and GI ulcers  Hypersensitivity reaction (<0.1%)  An unexplained increase in acute myocardial infarction in the dabigatran group versus warfarin (~0.2% increased risk for a AMI re-ly trial)
  80. 80. Contraindication “Recently the FDA added a contraindication to the dabigatran label against using the drug in patients with mechanical heart valves” [12/19/2012 - Drug Safety Communication - FDA] Based on A clinical trial in Europe (the RE-ALIGN trial) was recently stopped because dabigatran (Pradaxa) users were more likely to experience strokes, heart attacks, and blood clots forming on the mechanical heart valves than those were on warfarin. There was also more bleeding after valve surgery in the Pradaxa users than in the warfarin users.
  81. 81. Drug interaction  Concomitant use with P-glycoprotein inducers e.g. rifampin, st. john’s wart reduces its anticoagulant effect while inhibitors (e.g. amiodarone, verapamil & clarithromycin) can increase its plasma level  No other drug interactions are noted.
  82. 82. 1 RE-COVER  Primary outcome (recurrent VTE or death due to VTE): 2.4% vs. 2.1%  Mortality: 1.6% vs. 1.7% (p > 0.05)  Major bleeding: 1.6% vs. 1.9%; Major + clinically relevant bleeding: 5.6% vs. 8.8.% (p = 0.002) Trial design: Evaluated the safety and efficacy of dabigatran 150 mg twice daily (n 1274) vs. warfarin (n 1265) for the treatment of acute VTE. Patients were followed for 6 months. Results Dabigatran (n = 1,274) • Dabigatran 150 mg twice daily is noninferior to warfarin for the treatment of acute VTE, with a slightly better bleeding profile • Complements other studies showing safety and efficacy of dabigatran, as compared with warfarin in other settings, such as AF 2.4 2.1 % 0 4 (p < 0.001*) Conclusions Warfarin (n = 1,265) 1 2 3 Primary endpoint Major bleeding % (p = 0.38) 1.6 1.9 Schulman S, et al. N Engl J Med 2009;361:2342-52 5 * For noninferiority 0 4 1 2 3 5
  83. 83. Factor Xa inhibitors Rivaroxaban Apixaban
  84. 84. Rivaroxaban (Xarelto)
  85. 85. Rivaroxaban (Xarelto)  Direct factor Xa inhibitor  Half life: 7 - 9 hours  Peak plasma concentration 0.5 – 3 hours after administration  Have excellent bio-availability of 80-100%  2/3rd of rivaroxaban is metabolized by CYP3A4 system in liver  1/3rd of rivaroxaban excreted unchanged in urine while ½ of the metabolized excreted renally while other half via fecal route.
  86. 86. In contrast, bleeding from gastrointestinal sites, including upper, lower, and rectal sites, occurred more frequently in the rivaroxaban group, as did bleeding that led to a drop in the hemoglobin level or bleeding that required transfusion
  87. 87. Conclusion of ROCKET-AF trial “In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism with no significant difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group.”
  88. 88. Trial design: Patients with recent ACS(<7 days) were randomized in a 1:1:1 fashion to rivaroxaban 2.5 mg twice daily, 5 mg twice daily, or placebo, in addition to dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine in 93%. Patients were followed for 2 years. Results Conclusions (p = 0.008) Rivaroxaban 2.5 mg (n = 5,174) Primary efficacy endpoint 0 10 20 9.1 8.8 % Rivaroxaban 5 mg (n = 5,176) 10.7 Placebo (n = 5,176) ATLAS ACS 2−TIMI 51 • Primary endpoint: CV death/MI/stroke for rivaroxaban vs. placebo: 8.9% vs.10.7%, p = 0.008. True for 2.5 mg (9.1%) and 5 mg (8.8%) doses individually. Greatest efficacy for ischemic endpoints with the 2.5 mg daily dose, including mortality (2.9% vs. 4.5%, p = 0.002) • Non-CABG TIMI major bleeding: 2.1% vs. 0.6%, p < 0.001. Similar for 2.5 mg (1.8%) and 5 mg (2.4%) Mega JL, et al. N Engl J Med 2012;366:9-19 • Addition of very low dose rivaroxaban (2.5 mg twice daily) in patients with a recent ACS (most of whom were on DAPT) ↓ mortality, and ischemic events as compared with placebo. However, bleeding was simultaneously ↑ • First successful large trial with an oral anti-Xa agent in patients with ACS taking antiplatelet agents; use will require assessment of ischemia/bleeding risks
  89. 89.  To reduce the risk of DVTs and PEs in patients undergoing knee or hip replacement surgery (Jul 1, 2011)  For prevention of thromboembolism and stroke in patients with nonvalvular atrial fibrillation (Nov 4, 2011 )  Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as to reduce the risk of recurrent DVT and PE (Nov 2, 2012) Rivaroxaban: FDA Approval (First approved in July 1st, 2011)
  90. 90. Doses of rivaroxaban  Therapeutic dose : 20 mg once daily  Prophylactic dose : 10 mg once daily  No specific dose adjustment advised in moderate renal function impairment but it should be used with caution  Contraindicated in severe renal impairment  No dose adjustment required for body weight
  91. 91. Antidote  Like dabigatran, no specific antidote is available  Unlike dabigatran, rivaroxaban is not dialyzable because of a high degree of albumin binding in plasma (92%-95%)  Some effects are reversed by a 4-factor PCC (dose of 50 IU/kg) in case of acute major hospital or clinic bleeding, clinical data are still lacking
  92. 92. Rivaroxaban: drug interactions  CYP3A4 system realated  Inhibitors : Ketoconazole, ritonavir, clarithromycin, erythromycin (increase rivaroxaban levels 30-100%)  Inducers : Rifampicin (decrease rivaroxaban levels 50%)  P glycoprotein mediated  Inhibitors : amiodarone, verapamil & clarithromycin (increases rivaroxaban level)  Inducer : rifampin, st. john’s wart (decreases rivaroxaban level) So caution is advised but no dose adjustment are advised
  93. 93. Apixaban (Eliquis)
  94. 94. Apixaban (Eliquis)  Direct factor Xa inhibitor  Half life – 8 to 11 hours  Peak plasma concentration 1 – 3 hours after administration  Have excellent bio-availability of 66%  Metabolized in liver  25 % of apixaban is renally excreted, so no dose adjustment are required in renal failure pts  75% excreted by fecal route
  95. 95.  Apixaban only partially metabolized by CYP3A4 system, so strong CYP3A4 inhibitor/ inducer may affect its plasma level but this appears to be minimal as per its anticoagulants effect are concerned  Apixaban is minimally interact with P glycoprotein hence its effects are not affected significantly. Hence no clinically significant drug interactions
  96. 96. ARISTOTLE  Primary efficacy outcome (stroke/systemic embolism) for apixaban vs. warfarin: 1.27%/year vs. 1.6%/year; pnoninferiority < 0.001, psuperiority = 0.01  All strokes:1.19%/year vs. 1.51%/year, p = 0.01; all- cause mortality: 3.52%/year vs. 3.94%/year, p = 0.047  Primary safety outcome (ISTH major bleeding): 2.13%/year vs. 3.09%/year, p < 0.001 Trial design: Patients with atrial fibrillation (AF) and at least one additional risk factor for stroke were randomized to either apixaban 5 mg twice daily or dose-adjusted warfarin (titrated to a target INR of 2.0-3.0). Patients were followed for a median of 1.8 years. Results Conclusions Granger CB, et al. N Engl J Med 2011;365:981-92 (p < 0.001)* Apixaban (n = 9,120) Primary efficacy outcome • Landmark trial, demonstrates superiority of apixaban over warfarin in patients with AF for efficacy, with a significant reduction in bleeding 0 5 10 1.27 1.6 (p < 0.001) 2.13 3.09 5 Primary safety outcome Warfarin (n = 9,081) 0 10 %% * For noninferiority
  97. 97. 0 2 4 stroke AVERROES  Stroke or systemic embolism: 1.6%/year with apixaban vs. 3.7%/year with aspirin (p < 0.001)  Stroke: 1.6%/year vs. 3.4%/year (p < 0.001)  Clinically relevant nonmajor bleeding: 3.1%/year vs. 2.7%/year (p = 0.35)  Fatal bleeding: 0.1%/year vs. 0.2%/year (p = 0.53) Trial design: Patients with atrial fibrillation and elevated risk for stroke who were not suitable for warfarin therapy were randomized to apixaban 5 mg twice daily (n = 2,808) vs. aspirin 81-324 mg daily (n = 2,791).Median follow up was 1 yr Results Conclusions • Among patients with atrial fibrillation and elevated risk for stroke who were not suitable for warfarin therapy, apixaban was beneficial • Apixaban reduced the risk for the primary outcome of stroke or systemic embolism compared with aspirin, without increasing the risk for major bleeding Connolly SJ, et al. N Engl J Med 2011;364:806-17 (p < 0.001) Apixaban Aspirin %peryear Stroke or systemic embolism 1.6 3.7
  98. 98.  To reduce the risk of stroke and dangerous blood clots (systemic embolism) in patients with atrial fibrillation that is not caused by a heart valve problem (Dec 28, 2012 ) FDA recommendation (FDA first approved on Dec. 28, 2012)
  99. 99. Recommended Dose Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily. The recommended dose is 2.5 mg twice daily in patients with any 2 of the following characteristics: • age ≥80 years • body weight ≤60 kg • serum creatinine ≥1.5 mg/dL
  100. 100. Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery The recommended dose is 2.5 mg taken orally twice daily. The initial dose should be taken 12 to 24 hours after surgery. • In patients undergoing hip replacement surgery, the recommended duration of treatment is 35 days. • In patients undergoing knee replacement surgery, the recommended duration of treatment is 12 days.
  101. 101. Treatment of DVT and PE The recommended dose of ELIQUIS is 10 mg taken orally twice daily for 7 days, followed by 5 mg taken orally twice daily. Reduction in the Risk of Recurrence of DVT and PE The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least 6 months of treatment for DVT or PE.
  102. 102. How to treat with anticoagulants ?
  103. 103. Pts best treated with warfarin are… 1. Good level of control with warfarin 2. Renal failure pts 3. Mechanical heart valve replacement pts 4. Gastrointestinal disease pts & elderly pts 5. Poor compliance pts 6. Drug cost
  104. 104. 1. Good level of control with warfarin Why? ACC/AHA guideline noted that “Because of the twice daily dosing and greater risk of nonhemorrhagic side effects, patients already taking warfarin with excellent INR control (TTR≥65.5) may have little to gain by switching to dabigatran.” This recommendation suggests that patient values and preferences should influence the decision to initiate dabigatran.
  105. 105. A recent trial, in which patients with a stable warfarin dose were randomized to 4-weekly or 12-weekly INR testing demonstrated that the longer interval was noninferior for the primary outcome of TTR, This reduced INR monitoring frequency for selected patients further reduces the perceived inconvenience of warfarin treatment Blood. 2009;114(5):952-956.
  106. 106. 2. Renal failure pts Why ?  Patients with severe renal failure (CrCl ≤ 30 mL/min) were excluded from the RE-LY (dabigatran) and ROCKET AF trial. Dabigatran is mainly (80%) eliminated via the kidneys, while Rivaroxaban is less dependent on renal elimination. In the ROCKET AF trial, patients with a CrCl of 30 to 49 mL/min received a reduced dose of 15 mg daily. These observations suggest that warfarin remains the treatment of choice for patients with a calculated creatinine clearance close to or less than 30 mL/min
  107. 107. 3. Mechanical heart valve replacement pts Why ?  These new drugs have not been evaluated in patients with mechanical heart valve prosthesis  And also “ Recently the FDA added a contraindication to the dabigatran label against using the drug in patients with mechanical heart valves” [12/19/2012 - Drug Safety Communication - FDA]
  108. 108. 4. Gastrointestinal disease pts & elderly pts Why ?  Lower GI bleeding is significantly increased with dabigatran compared with warfarin (probably because of low bioavailability, which results in high concentrations of active drug in the feces)  Treatment with rivaroxaban was also associated with a significant increase of the risk for gastrointestinal bleeding  Hence, patients with intestinal angiodysplasia, inflammatory bowel disease, or diverticulosis, or those with a history of other forms of GI bleeding may experience a deterioration on treatment with dabigatran or rivaroxaban
  109. 109.  In the RE-LY trial, discontinuation of dabigatran was more frequent as a result of gastrointestinal distress, and 11.3% to 11.8% of patients on this drug complained of dyspepsia. This has been attributed to both tartaric acid contained in the capsule (required for absorption) and to a high concentration of active drug in the colon. This again suggests that dabigatran may not be an ideal agent for patients with a history of GI diseases.
  110. 110. 5. Poor compliance pts Why ?  Patients with documented poor adherence to the treatment with warfarin (OD dose) can not be seen as a candidate for dabigatran (BD dose)  Inability to monitor dabigatran (t1/2 14-17 hrs) or rivaroxaban (t1/2 11-13 hrs) coupled with its short half-life would imply that patients who are poorly compliant are at high risk of stroke because missing a dose will quickly experience a complete loss of antithrombotic efficacy. So first marker of noncompliance is probably stroke or other thrombotic complications.
  111. 111.  While For patients treated with warfarin and who undergo INR monitoring, the clinician is at least aware of inadequate levels, suggesting that aggressive measures to increase compliance can be put in place.
  112. 112. 6. Drug cost Why ?  Most common cause for non-compliance  Acquisition costs of novel agents will be higher than for warfarin  The estimated cost of one of the new agents already on the market is $3000 per year versus $50 per year for warfarin Circulation. 2011;123:2519–2521
  113. 113. Pts best treated with newer anticoagulants are… 1. Unexplained poor warfarin control 2. Poor level of control because of unavoidable drug- drug interaction 3. New patients on anticoagulation therapy for AF
  114. 114. 1. Unexplained poor warfarin control Why ?  Warfarin-experienced patients who continue to have variable INR results, corresponding to a TTR of less than 65%, have lower rates of stroke and other complications when treated with dabigatran 150 mg twice daily.  However, it is crucial to determine the reasons for instability because if instability is the result of noncompliance, warfarin remains the anticoagulant of choice
  115. 115. 2. Poor level of control because of unavoidable drug- drug interaction Why ?  Patients with frequent need for antibiotic treatment, chemotherapy, amiodarone, frequent use of acetaminophen, azathioprine, or a large number of concomitant medications, particularly if the exposure to these medications varies, will probably do better with the new anticoagulants.
  116. 116. 3. New patients on anticoagulation therapy for AF Why ?  For warfarin-naive patients who can afford newer agents, it is very tempting to go straight for the new anticoagulants to avoid the initial several weeks of frequent dose adjustments of warfarin But  Patients should be informed of the advantages and disadvantages of the alternatives & allowing them to make an informed decision on their preferred therapy.
  117. 117. Take Home Massage "Warfarin is not going to go away”  Patients with stable INRs in the therapeutic range may best be left on warfarin.  Others who better treated with warfarin are 1. Renal failure pts 2. Mechanical heart valve replacement pts 3. Gastrointestinal disease pts & elderly pts 4. Poor compliance pts 5. Drug cost  Groups of patients who should be candidates for the new drugs as: 1. Poor level of control because of unavoidable drug-drug interaction 2. New patients on anticoagulation therapy for AF 3. Unexplained poor warfarin control (it is important to establish that the unstable INR is not due poor compliance)  Dabigatran should be avoided in severe renal failure. Renal function is not so much of a problem with rivaroxaban .  For ACS patients, there are better data for rivaroxaban (in low dose) from the ATLAS trial.