Oral anticoagulant

Oral anticoagulant, classification, how o use, when to use, indications, side effects and guidelines

1. ORAL ANTICOAGULANTS Satya Mahapatra

2. Coagulation Pathways Harrison's 20 th edition

3. Classification of Anticoagulants

4. Classification of Oral Anticoagulants Coumarin Derivatives:- Warfarin Acenocoumarol (Acitrom ) Indandione Derivatives:- Phenindione Anisindione

5. Newer Oral Anticoagulants:- Direct Thrombin inhibitor – Dabigatron etexilate Direct factor Xa inhibitors:- Rivaroxaban Apixaban Edoxaban Betrixaban

6. Warfarin Coumarin derivative, water soluble vit K antagonist. Initially developed as rodenticide . Most wildly used anticoagulant in the world. Interfere the synthesis of vit K dependent clotting factor( factor II,VII,IX,X). It also reduces synthesis of vit K dependent anticoagulant proteins (protein C and S). Harrison's 20 th edition

7. Mechanism of action Harrison's 20 th edition

8. Continued….. Post translation modification add carboxyl group to the gama -carbon to generate Gama- carboxyglutamic acid. Post translational modification is essential for expression of activity of clotting factor because it permits Calcium dependent binding to negatively charged phospholipid surface. Warfarin inhibit VKOR( vit K epoxide reductase ) therefore blocking the carboxylation process. Harrison's 20 th edition

9. So only partially carboxylated clotting factors was synthesized and these have reduced or absent clotting activity. Anti thrombotic effect of warfarin depends on reduction in level of factor X and Prothrombin. Harrison's 20 th edition

10. Coagulation Factors Plasma half life(Hours) II 72-96 VII 4-6 IX 18-24 X 40-60 Protein C 8 Protein S 30 Plasma Half life of vit K dependent proteins Harrison's 20 th edition

11. Pharmacology of warfarin Racimic mixture of R and S isomers. S isomer is more active. Rapidly and completely absorbed from GIT. Peak levels in blood after 90 min of administration. Half life is 36-42 hours. >97% bound to albumin. Harrison's 20 th edition

12. Continued… Only unbound form is biologically active. Inactive metabolite excreted in urine and stool It accumulates in the liver and undergo CYP2C9 mediated oxidative metabolism. Common variant of CYP2C9, CYP2C9*2 and CYP2C9*3 encodes enzyme with reduced activity. Patient with these variant requires lower maintenance dose of warfarin. Harrison's 20 th edition

13. CYP2C9 Genotype effect on Anticoagulation CYP2C9 SNPs alter warfarin metabolism:- CYP2C9*1 (wild type)- normal activity. CYP2C9*2 – Low/intermediate activity. CYP2C9*3 – low activity. Approximately 25% of white have at least one variant allele of CYP2C9*2 or CYP2C9*3 and are less common in blacks and Asians. Harrison's 20 th edition

14. Warfarin dose reduction as follows:- Heterozygosity for CYP2C9*2 or CYP2C9*3 allele: 20-30% Homozygosity for CYP2C9*2 or CYP2C9*3 allele: 50-70% Harrison's 20 th edition

15. 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 reductions A/A : Homozygous- Requiring 50% dose reduction Asians have 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 CYP2C9 variants. Harrison's 20 th edition

16. Genotype Frequency in Asian Frequency in whites Frequency in African Americans Dose reduction compared to wild type Non- A/Non-A 7 37 82 -- Non -A/A 30 45 12 26 A/A 63 18 6 50 Frequency of VKORC1 haplotypes in different population and their effect on warfarin dose requirements Harrison's 20 th edition

17. Dosing Starting dose is 5-10 mg/day Lower doses require in: Elderly Heart failure Liver disease Renal impairment Malnutrition Thyrotoxicosis Patient on increased risk of bleeding( eg pt. on Aspirin) Asian patients High dietary intake of vit -K (green leafy vegetables eg . Broccoli) reduces the efficacy of Warfarin. Wintrobe’s clinical hematology

18. Wintrobe’s clinical hematology

19. Caution with vit -K containing food Health Canada recommends daily intake 90-120ug of vit -k. Different food contains different amount of vit k, since vit -K interfere the effect of warfarin, it is important to eat the same amount from day to day. Eat food with different levels of vitamin k.

20. Very high (>500ug/100 gm serving) High (100-500ug/100gm serving) Medium (25-100ug/100gm serving) Spinach Broccoli Cabbage. Seaweed Cauliflower Green beans Green tea Chick peas Green onions/tomato Lentils Wheat flour Soyabeans Coffee Pork liver Chicken liver

21. Concomitant parenteral anticoagulation with warfarin Warfarin has delayed onset of action. Parenteral anticoagulation should be given concomitantly in patients with established thrombosis or high risk for thrombosis until INR has been in therapeutic range for at least 2 days. Warfarin also decrease the anticoagulant proteins C and S thus increasing thrombogenic potential. Overlapping warfarin for at least 5 days with an immediately effective parenteral anticoagulants counteracts the procoagulants effects of unopposed warfarin. Harrison's 20 th edition

22. Commencement of warfarin therapy and monitoring Baseline INR<1.3, the patient will receive 5 mg of warfarin once daily on day1 and 2. INR is checked daily from day3 until therapeutic range of INR achieved and dose adjusted to achieve INR≥2. Then INR monitored 3 times weekly for 2 weeks INR monitored every 3-4 weeks when stable dose of warfarin achieved. INR maintained between 2-3 except in Mechanical heart valve where target INR 2.5-3.5. Harrison 20 th edition

23. J thromb Thrombolysis (2016) 41:187-207 Daneial M. Witt. Nathan P. Clark. Scott Kaatz .

24. PT-INR Warfarin therapy monitored using PT, a test sensitive to reduction in levels of Prothrombin, factor VII and X. This test involve addition of thromboplastin (reagent containing tissue factor, phospholipid and ca++) to citrated plasma and determining the time to clot formation. Thromboplastin vary in their sensitivity to reduction in the levels of the vitamin k dependent clotting factors . Harrison's 20 th edition

25. Continued… INR represent the PT according to international reference thromboplastin, as approved by WHO . Highly sensitive thromboplastin have an ISI of 1.0 Most current thromboplastin have ISI values between 1.0-1.4 Harrison's 20 th edition

26. Indications Atrial fibrillation Prosthetic heart valve Venous thromboembolism Primary pulmonary hypertension. Rarely after acute MI.

27. Side effect of warfarin Bleeding Skin necrosis Purple toe syndrome Teratogenicity Osteoporosis Others: Agranulocytosis, leucopenia, diarrhea, anorexia.

28. Bleeding Most common complication. Mild : epistaxis, hematuria Severe: Retroperitoneal or GIT Life threatening: intracranial bleed. Rate of major bleeding is 1-3%. Half of complications occurs when INR exceeds therapeutic range .

29. 2017 ACC on management of bleeding in patient on OACs

30. 2017 ACC on management of bleeding in patient on OACs

31. Drugs and medical condition affecting Warfarin potency Potentiator Antagonist Drugs Medical condition Drugs Medical condition Acetaminophen Older age Carbamazepine Excess vit -k Omeprazole liver disease Chlordiazepoxide Hypothyroidism Propanolol Malabsorption Rifampicin Nephrotic syndrome Phenytoin Hyperthyroidism Barbiturates Broad spectrum Fever Antibiotics Vit -K deficiency Adrenal corticosteroid Fluconazole CHF Sucralfate Indomethacine Malnutrition Lovastatin Protease inhibitor Wintrobe’s clinical hematology

32. Warfarin in special conditions Pregnancy: contraindicated in 1 st (teratogenic) and 3 rd trimester(intracranial bleeding chances increases). Does not passes in milk therefore safe for nursing mother. Modification before surgery:- Pt. on long term anticoagulation with warfarin - stop it 5 days prior to surgery. Those who are high risk for TE can be bridged with LMWX. Last dose of LMWX should be given 12 or 24 hour before surgery. Those receiving bridging anticoagulation with therapeutic dose UFH, should be stopped 4-6 hour before surgery. Harrison's 20 th edition

33. Continued.. INR checked on day of surgery. Heparin resumed about hours after procedures if there is adequate hemostasis. Warfarin can be resumed, at the normal maintenance dose, at evening of surgery or next morning if adequate hemostasis . OACs should not be stopped in majority of patient requiring skin biopsy, out patient dental surgery including dental extraction. NSAIDS should not prescribed following dental surgery in patient of warfarin . Harrison's 20 th edition

34. Warfarin in Venous Thromboembolism Warfarin should be initiated concurrently with parenteral heparin. For VTE patients target INR range 2-3. After 5 days, warfarin should be continued for at least 3 month. Optimal duration depends on clinical settings.

35. Optimal Duration of Anticoagulants Clinical Course Recommendations 1 st provoked PE/Proximal leg DVT 3-6 month 1 st provoked upper extremity DVT or isolated calf DVT 3 month 2 nd provoked VTE Uncertain 3 rd VTE Indefinite duration Cancer and VTE Consider indefinite duration or until cancer is resolved. Unprovoked PE/Proximal leg DVT Consider indefinite duration 1 st unprovoked calf DVT 3 month 2 nd unprovoked calf DVT uncertain

36. Acenocoumarol (Acitrom) Short half life of 10-16 hours. More rapid onset. Shorter duration of action (2 days) Dose 4 mg on D1, 4-8 mg on D2 then maintenance dose of 1-8 mg according to response by PT test. Anticoagulant quality is slightly lesser than warfarin.

37. Newer Oral anticoagulants Why there is need of newer anticoagulants…. Limitation of Warfarin:- Narrow therapeutic range. Slow onset of action. Slow offset of action. Multiple drug and dietary interaction. Monitoring required to maintained in therapeutic range. Difficult to manage for invasive procedures. Adverse events and complexity of management. Wintrobe’s clinical hematology

38. Attributes of Ideal Anticoagulants Oral administration Rapid onset of action/rapid offset of action. Wide therapeutic range Predictable therapeutic effect. No food or drug-drug interaction No monitoring required. Easily reversible. Cost effective. Well defined pharmacokinetics in presence of renal or hepatic disease. European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

39. Dabigatron etexilate Oral direct thrombin(factor IIa ) inhibitor. Prodrug which is hydrolyzed and form Dabigatron (active moiety). Initially recommended by FDA on Oct, 19 2010 for Non- Valvular AF. Competitive, direct thrombin inhibitors. Both free and clot bound thrombin, and thrombin induced platelet aggregation are inhibited by active moieties. Oral bioavailability ≈ 6-7%. Uptake is reduced by PPI and absorption delayed when taken with food. Wintrobe’s clinical hematology

40. Continued… Peak level after 2 hours of oral dose. Primarily eliminated by renal clearence . Half life 14-17 hours. Concurrent administration of p- gp inhibitors (Ketoconazole, Quinidine) and inducer (Rifampicin) not advisable. Contraindicated with CrCl <15ml/min. Monitoring of therapy not required.

41. Continued ….. Side effects : Bleeding, Dyspepsia, higher GI bleeding and myocardial ischemia as compared to warfarin. In case of overdose, rapid administration of charcoal may decrease absorption and hemodialysis can remove 60 % of plasma drug level. Approved in India since Dec 2011 for stoke/systemic embolism prophylaxis in non- valvular AF patient For prevention of venous thromboembolic events in patient undergoing orthopedic surgery from feb 2013 by CDSCO. Wintrobe’s clinical hematology

42. Algorithm for starting Dabigatron European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

43. Rivaroxaban First oral direct factor Xa inhibitor. Reversible direct factor Xa inhibitor that bind and to inactivate both plasma factor Xa and clot bound factor Xa. Bioavailability : 60-80 % Peak action 2-3 hours. Half life: 7-11 hours. Metabolized by CYP3A4 dependent and independent pathways. Potent combined P- gp and CYP3A4 inhibitors (ketoconazole,PI) and inducer (Carbamazepine, Phenytoin, Rifampicin) should be avoided. Wintrobe’s clinical hematology

44. Algorithm for Indication, dosing and interactions of Rivaroxaban . European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

45. Continued.. Approved for VTE(CDSCO) prophylaxis in post op cases of THA/TKA since Jan 2010. Approved for prevention of atheroembolic events in adult patients after an ACS with elevated cardiac marker from july 2015. Pregnancy category C. Available as Xarleto (Bayer pharma).

46. Apixaban Reversible direct factor Xa inhibitor that bind and to inactivate both plasma factor Xa and clot bound factor Xa. Oral bioavailability >45%. Peak level after 3 hour of oral intake. Half life 8-14 hours. Eliminated via multiple mechanism(predominantly via liver) Potent combined P- gp and CYP3A4 inhibitors (Ketoconazole, PI) and inducer (Carbamazepine, Phenytoin, Rifampicin) should be avoided. Pregnancy category B Approved for prevention of stroke in non- valvular AF patients by FDA in Dec 2012 . Wintrobe’s clinical hematology

47. Continued… Approved for prevention of VTE for hip and knee replacement surgery (CDSCO). Approved for treatment of DVT and PE in adult patient in may(CDSCO).

48. Indications, dosing and Interaction of Apixaban European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

49. Edoxaban Another reversible direct factor Xa inhibitor. Reaches peak plasma level within 1– 2 hr. 50% excreted through kidney and rest through multiple mechanism. Associated with lower rate of bleeding, including major bleeding, intracranial bleeding. GI bleeding more frequently than warfarin when used with high dose but less frequently with low dose. Patient with CrCl <30 ml/min, high risk of bleeding, use of dual antiplatelet, ACS, and stroke with 30 days were excluded.

50. Continued.. Pregnancy Cat C. No antidote FDA approved in Jan to prevent embolic events in non- valvular AF. Available doses:15,30,60 mg

51. Algorithm for Indicatons, dosing and interactions of Edoxaban

52. Other factor Xa inhibitors Betrixaban:- Approved by FDA on Oct 2015 for VTE prophylaxis in hospitalized medically ill patients at risk of thromboembolism. Excreted through bile, can be given to ESRD . Minimal drug interactions. Doses 160 mg on D1 f/b 80mg/day for 35-42 days. Darexaban (YM-150):- Discontinue in sep 2011 . TAK 442: In trial phase .

53. Reversal Agents IDARUCIZUMAB: Fully humanized antibody fragments that binds dabigatron with high affinity and specificity. FDA approved its use in Oct 2015. REVERSE-AD Trial shows its beneficial effect in reversing effect of Dabigatron in patient with severe bleeding or who require urgent procedure with in 4 hours . Available as Praxbind. ANDEXANET ALFA: Recombinant modified human factor Xa reversal agent. It rapidly attenuate the anti factor-Xa activity of Apixaban, Rivaroxaban, Edoxaban, Enoxaparin . well tolerated and currently in phase 3 trial.

54. Continued.. CIRAPARANTAG(PER977): Water soluble non-specific reverse agent . In preclinical testing and during testing with Edoxaban in healthy male volunteers.

55. Use of Anticoagulants according to patient characteristic Patient charactertics NOAC Dose regimen High risk of Stroke (High CHADS-VASC score) Dabigatron 150 mg BD Previous stroke Rivaroxaban 20 mg OD High risk of bleeding or previous life-threatening bleeding Dabigatron Apixaban 110 mg BD 5 mg BD Dyspepsia Rivaroxaban Apixaban 20 mg OD 5 mg BD GI Bleeding Apixaban 5 mg BD Medication compliance problem Rivaroxaban 20 mg OD Elderly (>80 year) and impaired renal function Apixaban 2.5 mg BD European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

56. Pre and Postoperative management of patients taking NOACs European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

57. Recommendation on how to switch between different anticoagulant regimens Switching How? VKA to NOACs Once the INR lower than 2 Intravenous UFH to NOAC After 2 hr of stopping UFH(longer in case of renal impairment) LMWH to NOAC When the next dose of LMWH was advised NOAC to VKA Concomitant treatment until INR 2-3 NOAC to Parenteral anticoagulant (UFH, LMWH) When next dose of NOAC was planned One NOAC to another When the next dose of NOAC was planned( longer in case of renal impairment) European Heart J cardiovascular Pharmacotherapy (2015)1 (2): 134-145

58. Oral Anticoagulants in AF AF and an CHA2DS2-VASc score of >2 in men or >3 women, OAC recommended.(COR I, LOE A). NOACs (Dabigatron, Rivaroxaban, Apixaban, and Edoxaban) are recommended over warfarin in NOAC-eligible patients with AF(I A) Warfarin preferred - moderate-to-severe mitral stenosis or a mechanical heart valve(I B). With warfarin measure INR -at least weekly during initiation of anticoagulant therapy and at least monthly when anticoagulation (INR in range) is stable(I A). Renal and hepatic function- Evaluate before initiation of a NOAC and re- evaluate at least annually(I B). AF ( CHA2DS2-VASc Score > 2 in men or >3 in women) with CKD ( ESRD;CrCl <15 mL /min) Warfarin (INR 2.0 to 3.0) or Apixaban ( IIb -B). ACC/AHA 2019 guideline

59. ACC/AHA 2019 guideline

60. Thromboembolism Prevention In AF AF or Atrial flutter ≥ 48 hrs or of unknown duration: Warfarin (INR 2.0 to 3.0),factor Xa inhibitor, direct thrombin inhibitor is recommended for at least 3 weeks before and at least 4 weeks after cardioversion,(regardless of the CHA2DS2-VASc score or the method used to restore sinus rhythm)[I B-R] Who have not been anticoagulated for the preceding 3 weeks, do TEE before cardioversion and proceed with cardioversion if no left atrial thrombus is identified, including in the LAA( IIa B) AF or Atrial flutter <48 hrs and CHA2DS2-VASc Score >2(men) and < 3 (women): warfarin (INR 2.0 to 3.0), factor Xa inhibitor, direct thrombin inhibitor is recommended as soon as possible before cardioversion ,followed by long-term anticoagulation therapy( IIa B) ACC/AHA 2019 guideline

61. Thank You