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Warfarin - Oral Anticoagulant

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Warfarin. Most used oral anticoagulant in the world. In some cases it has no alternative. Has many side effects. Careful monitoring and judicious titration of dose can make it best. Live long …

Warfarin. Most used oral anticoagulant in the world. In some cases it has no alternative. Has many side effects. Careful monitoring and judicious titration of dose can make it best. Live long Warfarin.

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  • 1. Dr. Md. Arifur Rahman Sazal MBBS, MD (Cardiology) Clinical & Interventional Cardiologist National Institute of Cardiovascular Diseases Dhaka, Bangladesh
  • 2. WARFARI N
  • 3. A brief history of warfarin  The discovery of oral anticoagulants is one of the most mysterious story in pharmaceutical history.  It started with a hemorrhagic disease in cattle in the Midwest US in the 1920s. This was due to ingestion of spoiled sweet clover. The substance responsible for bleeding was extracted and identified as a coumarin by Karl Paul Link from University of Wisconsin.  In 1941 it used as a rat and mouse poison, but the survival of a man suffering from thromboembolic disease after an attempted suicide by the use of a large amount of warfarin- based rodenticide led to clinical trials of warfarin (Wisconsin Alumni Research Foundation,WARF), which was approved for medical use in 1954.
  • 4. Sweet clover sweet smell but bitter Systematic name (RS)-4-hydroxy- 3-(3- oxo- 1-phenylbutyl)- 2H- chromen- 2-one
  • 5. Mechanism of action
  • 6. Routes Oral Bioavailability 100% Protein binding 99.5% Metabolism Hepatic: CYP2C9, 2C19, 2C8, 2C18, 1A2 and 3A4 Half-life 40 hours Excretion Renal (92%) Pregnancy cat. D Pharmacokinetic data
  • 7. Condition INR range Preventing DVT (high risk patients, like those who have had hip replacement) 2.0-3.0 Therapy after DVT or pulmonary embolism 2.0-3.0 Preventing systemic embolism - Atrial fibrillation -Valvular heart disease -Tissue heart valves (first 3 months) 2.0-3.0 2.0-3.0 2.0-3.0 Bileaflet mechanical heart valve (aortic) 2.5-3.5 Mechanical prosthetic heart valve (high risk) 3.0-4.5 Thrombosis in antiphospholipid antibody syndrome Indication with target INR
  • 8. Contraindication
  • 9. Increased bleeding risk due to increased effect of warfarin: ➞ INR Antiarrhythmics - amiodarone , propafenone Antibiotics - amoxicillin , cephalosporins , fluoroquinolones, macrolides. Anticonvulsants - phenytoin ,sodium valproate Antidepressants -duloxetine ,venlafaxine, SSRI. Antifungals- fluconazole , itraconazole , ketoconazole. Antihyperlipidemics - Ezetimibe , fenofibrate ,Atorvastatin, fluvastatin ,rosuvastatin Decreased effect warfarin:➞INR Antibiotics - rifampin Antidepressants- trazodone Antiepileptics - carbamazepine , phenobarbitone ,phenytoin. Drug interaction
  • 10.  Vegetables that include cauliflower, kale, Brussels sprouts, asparagus, spinach, alfalfa, turnip greens, mustard greens and collard greens  Beverages such as herbal teas (green tea) and coffee.  Vegetable oils that include soybean, olive.  Peas and green onions  Dairy products such as yogurt Vitamin K ,Foods to Avoid while on Warfarin
  • 11. Complications of Warfarin Hemorrhage- 2.7% (major- 1.1%-8.1%) Warfarin Embryopathy -5% -30% Warfarin necrosis- 0.02% Osteoporosis- 0.1% Purple toe syndrome-0.01%
  • 12. Warfarin Embryopathy (WE) -Di Sala syndrome A specific pattern of congenital anomalies develop in children born to mothers exposed to warfarin during the first trimester of pregnancy (between the 6th and 12th weeks of gestation). Classical features of WE- Nasal hypoplasia Chondrodysplasia punctata (epiphyseal and vertebral bone stippling) Less frequent malformations- Intraventricular hemorrhage Hydrocephalus Cervical spine myelopathy Finger and toe defects
  • 13. Calcifications and irregular ossification of lumbar and sacral vertebrae Chondrodysplasia punctata
  • 14. 21-week stillborn with warfarin embryopathy, extreme nasal hypoplasia.
  • 15. Nasal hypoplasia
  • 16. Warfarin necrosis  The onset is usually within the first 2 to 5 days of warfarin therapy, when the blood tends to clot more than is normal.  Skin necrosis affects areas of the body with a high fat content, such as breasts, thighs, buttocks, hips and abdomen. .  It affects 1 in every 10,000 patients prescribed warfarin.
  • 17. D/D of Warfarin necrosis: Pyoderma gangrenosum ,,Necrotizing fasciitis.
  • 18. Mechanism of Warfarin necrosis Warfarin Inhibition of protein C ( natural anticoagulant) Coagulation factor imbalance Paradoxical activation of coagulation Thrombosis Skin necrosis.
  • 19. Purple toe syndrome  Warfarin cause violaceous painful discoloration of the toes and the sides of the feet . This typically happens within the first few weeks of starting warfarin  The problem appears to occur mostly in elderly people and in people with underlying arteriosclerosis. bleeding into atheromatous plaques in the blood vessel wall leads to the release of cholesterol clumps that embolize to the hands and feet, leading to obstruction of small arteries.
  • 20. Purple toe syndrome
  • 21. Osteoporosis and Warfarin  Warfarin indirectly weaken bones, because vitamin K is involved with the protein osteocalcin, which is important for bone remineralization .
  • 22. Warfarin in special situations
  • 23. Warfarin in pregnancy  Warfarin cross the placenta and should be avoided during the first and third trimesters.  Treatment at 6-12 weeks gestation causes Warfarin embryopathy.  Later exposure is associated with central nervous system abnormalities.  Almost 5%- 30% of children (10 of 35) born to mothers with a prosthetic heart valve were malformed .Heparins do not cross the placenta and do not cause these problems.  It is safe to breastfeed during warfarin therapy as there is minimal excretion into breast milk.
  • 24. Warfarin in Prosthetic heart valves The ACCP recommends  Bileaflet or tilting disc valves- INR -2.0-3.0 –life long.  Caged ball or disc- 2.5-3.5- life long.  Bioprosthetic (tissue) valve require three months of warfarin -INR -2.0-3.0.  Combination of aspirin (100 mg/day) with warfarin reduces the risk of systemic embolism.
  • 25. Venous Thromboembolism ( DVT and PE )  Target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows: For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended.  For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended
  • 26. Warfarin in liver disease  Warfarin is associated with a 0.8% to 1.2% risk of transaminase elevation >3 ULN .  Liver damage in Hepatitis C could be treated with warfarin.  Warfarin reduces the scarring on the liver caused by Hepatitis C.  In Hepatitis C, scarring of the liver accelerates in those patients who are prone to form blood clots.. http://www.news-medical.net/news/2011/07/31/40407.aspx
  • 27. Warfarin in Renal impairment  There is no evidence that response to Warfarin is altered in renal impairment , thus dosage adjustments are generally not necessary.  However, patients with renal impairment may cause platelet defects and may increase risk for bleeding.  Patients with CKD required on average a 25% reduction warfarin dose. Journal of the American Society of Nephrology (JASN). April 2009
  • 28. Antithrombotic Therapy in Cardioversion for Atrial Fibrillation Timing of cardioversion Anticoagulation Early cardioversion in patients with AF for < 48 hrs Heparin during cardioversion period to achieve PTT of 1.5 to2.5 times the baseline value Early cardioversion in patients with AF for > 48 hrs or an unknown duration, but without documented atrial thrombi Heparin during cardioversion period to achieve PTT of 1.5 to 2.5 times the baseline value. Warfarin for 4 weeks after cardioversion to achieve target INR of 2.5 (range: 2.0 to 3.0) Elective cardioversion in patients with AF >48 hrs or an unknown duration Warfarin for 3 weeks before and 4 weeks after cardioversion to achieve target INR of 2.5 (range: 2.0 to 3.0)
  • 29. CHADS2 score Condition Points C Congestive heart failure 1 H Hypertension: blood pressure consistently above 140/90 mmHg (or treated hypertension on medication) 1 A Age ≥75 years 1 D Diabetes mellitus 1 S2 Prior Stroke or TIA 2 Total 6 Guidelines for the management of atrial fibrillation Estimating the risk of stroke
  • 30. CHA2DS2 VASc score European Heart Journal (2010) 31, 2369–2429doi:10.1093/eurheartj/ehq278
  • 31. Score Risk Anticoagulation Therapy Considerations 0 Low No antithrombotic therapy (or Aspirin) No antithrombotic therapy (or Aspirin 75-325mg daily) 1 Moderate Oral anticoagulant (or Aspirin) Oral anticoagulant, either new oral anticoagulant drug Dabigatran or well controlled warfarin at INR 2.0-3.0 (or Aspirin 75-325mg daily. 2 or greater High Oral anticoagulant Oral anticoagulant, using either a new oral anticoagulant drug (Rivaroxaban or Dabigatran) or well controlled warfarin at INR 2.0-3.0 Anticoagulation (CHA2DS2 VASc score) European Heart Journal (2010) 31, 2369–2429doi:10.1093/eurheartj/ehq278
  • 32. Warfarin monitoring- Recommended INR testing guidelines
  • 33. Managing overdose and bleeding of warfarin therapy Clinical setting Action INR >5.0 but < 9.0 (no bleeding) Stop warfarin, 1-2.5mg vitamin K1, INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5. INR ≥9.0 (no bleeding) Stop warfarin, 5mg vitamin K1, measure INR in 6-12 hours, restart warfarin at reduced dose once INR is < 5, clotting factor replacement- if high risk of bleeding Major bleeding (any level of INR) Stop warfarin, give 5mg vitamin K1, clotting factor replacement, measure INR as required, assess need to restart warfarin
  • 34. Future challenges for Warfarin ?
  • 35. Property Dabigatran Warfarin Indication for AF Non-valvular atrial fibrillation Valvular or non-valvular atrial fibrillation Mechanism of action Direct inhibition of thrombin Reduced synthesis of prothrombin and other clotting factors Administration Oral Twice daily (for AF) Oral Once daily Dosing Fixed dose, dependent on creatinine clearance and age Individualised to each patient and target INR Onset of action 0.5–2 hours 36–72 hours Elimination half-life 12–14 hours 20–60 hours Duration of action 24 hours 48–96 hours Comparison of Dabigatran and Warfarin
  • 36. Property Dabigatran Warfarin Stable, predictable pharmacokinetics Yes No Interactions with diet and alcohol No Yes Interactions with medicines Interactions largely unknown, clinical experience over time likely to reveal more. Known interaction with p-glycoprotein inhibitors e.g. oral ketoconazole, verapamil, amiodarone Multiple Monitoring No routine monitoring required. INR every one to eight weeks depending on clinical situation Comparison of dabigatran and warfarin
  • 37. Property Dabigatran Warfarin Risk of major haemorrhage Similar for both medicines Major GI bleeding rates may be higher than with warfarin, however, rates of intracranial haemorrhage and life-threatening bleeding may be lower with dabigatran. Similar for both medicines. Other adverse effects Dyspepsia Possibly increased risk of MI Multiple reported, however, in clinical practice these are relatively rare Antidote None available but can be removed by dialysis Vitamin K Fresh-frozen plasma Cost Very expensive- 450 $/ month Very cheap- 30 $/ month Comparison of dabigatran and warfarin
  • 38. Trials designed to compare the new oral anticoagulants to prevent thromboembolism with warfarin in AF Trial Study drug Dosing Number of patients Design RE-LY Dabigatran 110 mg twice daily, 150 mg twice daily 18,113 Randomized, open-label, noninferiority Rocket-AF Rivaroxaban 15 mg daily, 20 mg daily 14,000 Randomized, double blind, noninferiority ARISTOTLE Apixaban 5 mg twice daily 15,000 Randomized, double blind, noninferiority Engage AF Edoxaban 30 mg daily, 60 mg daily 16,500 Randomized, double blind, noninferiority Altman and Vidal Thrombosis Journal 2011 9:12 doi:10.1186/1477-9560-9-12
  • 39. The evidence for dabigatran - RE-LY trial The Randomised Evaluation of Long-Term Anticoagulation Therapy Large, randomised, non-inferiority clinical trial Event % of incidents per year Significance (P ≥ 0.05) Dabigatran 110 mg Dabigatran 150 mg Warfarin Stroke or systemic embolism 1.53 1.11 1.69 D150 superior to W D110 not inferior to W D150 superior to D110 Myocardial infarction 0.72 0.74 0.53 W superior to D150 Intracranial haemorrhage 0.23 0.30 0.74 D110 superior to W D150 superior to W Life-threatening bleeding 1.22 1.45 1.80 D110 superior to W D150 superior to W Gastrointestinal bleeding 1.12 1.51 1.02 W superior to D150 D110 superior to D150 Death from vascular causes 2.43 2.28 2.69 D150 superior to W Death from any causes 3.75 3.64 4.13 No difference
  • 40. New hope Pharmacogenetics based warfarin therapy
  • 41. Pharmacogenetics based warfarin therapy
  • 42. Pharmacogenetics based warfarin therapy
  • 43. Mr. Shakil 64 inch 58 kg 03 .08. 69 Dr. Tazkera Mr. Atik
  • 44. Pharmacogenetics based warfarin therapy
  • 45. Conclusion Warfarin took more than 20 years to establish its existance as an effective and adjustable anticoagulant . Physicians has more than 40 years of experience to use it It is now in good shape with vast knowledge of handling it Furthermore Pharmacogenetics based warfarin therapy is getting popularity. Newer anticoagulants are in different phases of their trials . Many more informations and results are still pending -so it will not be so easy to replace warfarin by newer anticoagulants so early.
  • 46. Live long Warfarin Thank you Dr.Arif

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