Oral anticoagulant

Warfarin and newer oral anticoagulants e.g. debigatran, rivaroxaban, apixaban were presented in cardiology morning session in Bangabandhu Sheikh Mujib Medical University.

1. Oral anticoagulant Dr. Md. Mashiul Alam Phase B Resident University cardiac centre BSMMU 20 Oct, 2015

2. Over view of Hemostasis

3. Over view of Hemostasis

4. Over view of Hemostasis Platelet activation

5. Over view of Hemostasis Coagulation Casecade

6. Oral Anticogulants Old- Warfarin (Inhibit formation of Factor Prothombin , VII, IX, X) New- 1. Debigatran (Direct Thrombin Inhibitor) 2. Rivaroxaban 3. Apixaban Direct Factor Xa Inhibitor

7. Warfarin

8. Pharmacokinetic data Route Oral Bioavailability 100% Protein binding 99.5% Half Life 40 hours Excretion Renal (92%) Pregnancy category D

9. Indication Therapeutic INR 2.5 Prevention and treatment of VTE Arterial embolism AF with stroke risk factor Post MI mobile mural thrombus Extensive anterior MI DCM Cardioversion Ischemic stroke in antiphospholipid syndrome MS and MR with AF

10. Indication cont’d… Therapeutic INR 3.5 Recurrent venous thrombosis whilst on warfarin Mechanical prosthetic cardiac valves

11. Contraindication

12. Drug Interaction Increased bleeding risk with warfarin : 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

13. Drug interaction Decreased therapeutic effect of warfarin : Antibiotics - Rifampin Antidepressants- Trazodone Antiepileptics - Carbamazepine , phenobarbitone , phenytoin .

14. Food to avoid while on Warfarin 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

15. Complications Hemorrhage- 2.7% (major- 1.1%-8.1%) Warfarin Embryopathy -5% -30% Warfarin necrosis- 0.02% Osteoporosis- 0.1% Purple toe syndrome-0.01%

16. Some facts about warfarin It is safe to breastfeed during warfarin therapy as there is minimal excretion into breast milk . Warfarin reduces the scarring on the liver caused by Hepatitis C. Dosage adjustments are generally not necessary in renal impariment . Patients with CKD required on average 25% reduction of warfarin dose .

17. What’s wrong with traditional anticoagulants

18. Traditional anticoagulants have 2 major limitations : Narrow therapeutic window of adequate anticoagulation without bleeding Highly variable dose-response, requiring monitoring by lab testing

19. 3 new oral anticoagulants (NOAC) Debigatran Rivaroxaban

20. Apixaban

21. Indication 1. Prevention of venous thromboembolism in a patient undergoing total hip or knee replacement 2. Prevention of stroke or systemic embolism in patients who have non-valvular atrial fibrillation and has one or more risk factors for developing stroke or systemic embolism 3. Rivaroxaban for the prevention of recurrent venous thromboembolism and for the treatment of deep vein thrombosis and pulmonary embolism.

22. Contraindication Known hypersensitivity to ingredients of NOAC Clinically significant active bleeding Renal impairment GFR <30ml/min Hepatic disease. (Child Pugh – C) Recent high risk bleeding lesion ( eg . ICH < 6 months) Pregnancy or breast feeding Recent stroke, surgery, GI bleed or ulcer Recent fibrinolytic therapy <10days Concomitant warfarin therapy

23. Prescribing an NOAC 1. Detailed History EXCLUSION Criteria: - Known hypersensitivity to NOAC preparation - Pregnant or breastfeeding - Stable warfarin therapy - Prosthetic heart valve - Recent stroke

24. 3. Assess bleeding risk -Disorder of haemostasis -Recent surgery (≤ 1 month ago) -GI bleed ≤ 12 months ago -Ulcer ≤ 30 days ago - Fibrinolytic treatment last 10 days -Dual antiplatelet therapy

25. 3. Lab tests – FBC, U&E, LFTs Contraindications : -Poor renal function ( CrCl ≤ 30 mL / min, apixaban : ≤ 15 mL /min) -Liver disease (e.g. ALT > 3x upper limit of normal) - Hb ≤ 10 g/ dL

26. 4. Is patient on warfarin ? Stop warfarin Start a new oral anticoagulant when INR is < 2

27. Limitations of NOAC Cost is high though cost effective than warfarin . ( Debigatran vs warfarin -450$/ month vs 30$/ month) No antidote available right now though can be removed by dialysis. New antidote is under phase II trial. Possibly increased risk of MI major GI bleeding may be higher. Carefully selected patients for Phase III trial are not representative of real world data . More Phase IV trials are needed until then it should be used in selected patients .

28. Advantages over warfarin Stable and predictable pharmacokinetics No interaction with diet and alcohol No significant drug interaction apart from ketoconazole , amiodarone , verapamil No monitoring required Intracerebral and life threatening bleeding rates are lower than warfarin .

29. Thank you