Anticoagulants How much, which one & how long? Stephanie M. Dentoni, MD,FSVM California Vein & Vascular Institute

I Have No Financial Interests To Disclose

Practical Use of Novel Anticoagulants

Objectives and Goals Introduce Novel Anticoagulant Review Practice Pharmacokinetics Outline Indications with Respect to VTE Warnings and Side Effects Discuss Practical Usage Clinical Pearls

Overview of Anticoagulants Heparin was first discovered in 1916 by Jay Mc Lean and William Harry Howell Use of heparin in clinical practice was 20 years later Low molecular weight heparin was discovered in 1976 with clinical trials starting in the early 1980’s Sweet clover disease lead to the discovery of the first oral anticoagulant: dicourmarol Now, the turn of the century there are several oral anticoagulants available for use

Limitations of Traditional Anticoagulants Subcutaneous administration Difficult to administer - subcutaneous Limits long term use Long half-life Bleeding complications Monitoring Slow Onset warfarin Variable dosing Warfarin/food and drug interactions Accumulation with renal insufficiency LMWH Heparin Induced Thrombocytopenia

Benefits of New Oral Anticoagulants Specific target in the coagulation cascade Factor II Factor X Predictable dose response Ease of administration No monitoring required Short half life No significant food interactions Less drug interactions

Novel Oral Anticoagulants Dabigatran Rivaroxaban Apixaban Edoxaban

Dabigatran

Dabigatran Prodrug – dabigatran etexilate Reversibly inhibits the active site of thrombin Bioavailability of 6% Peak plasma levels = 2 hours Half-life 14 - 17 hours Renal excretion Concomitant use of quinidine is contraindicated due to increasing plasma levels of dabigatran by reducing clearance Reduced dose recommended with co-administration of amiodarone and verapamil

Dabigatran Indications Nonvalvular Atrial Fibrillation Prevention of venous thromboembolism Treatment of venous thromboembolism

Dabigatran Dosing 150mg po twice daily 110mg po twice daily for special populations Greater than 80 years old Concomitant use of verapamil

Dabigatran Administration Oral With or without food Swallowed with water Capsule should not be broken or opened Increased bioavailability Increased risk of bleeding

Missed Dose of Dabigatran Can take dose up to 6 hours prior to next scheduled dose Do not double dose Do not take missed dose within 6 hours of the next dose

Laboratory Values and Dabigatran aPTT is elevated aTT is elevated ECT is elevated INR is abnormal Cannot determine the amount of anticoagulant or the level TT and ECT may be useful for monitoring but studies are needed

Start dabigatran 0-2 hours prior to next dose of LMWH Treatment for VTE 5 days of LMWH Start dabigatran 0-2 hours prior to next dose of LMWH

Contraindications for Dabigatran CrCl less than 30 Clinically significant bleeding Lesion or medical condition considered high risk for bleeding Concomitant administration with other anticoagulants Hepatic or liver impairment that will have an impact on survival Concomitant treatment with ketaconazole, itraconizole, cyclosporin, dronedrone Prosthetic heart valves Pregnancy or breast feeding

Transferring from Warfarin to Dabigatran Stop Warfarin When INR falls below 2, start dabigatran

Rivaroxaban

Rivaroxaban Direct Xa inhibitor Oral bioavailability of 80% Rapid onset with half-life of 7-11 hours Elimination: 1/3 unchanged through renal excretion 1/3 via the liver CYP3A4 dependent and independent pathways with fecal excretion 1/3 metabolized in the liver with inactive metabolites and excreted through the kidneys

Contraindications with Rivaroxaban Active, severe bleeding Severe hypersensitivity reaction to rivaroxaban

Warnings Rivaroxaban Not approved for prosthetic heart valves Combined P-gp and strong CYP3A4 inhibitors and inducers significantly alter the anticoagulant effect ketaconazole and ritonavir Use with caution in pregnancy due to bleeding risk Avoid concomitant use of other anticoagulants

Indications Nonvalvular atrial fibrillation Treatment of DVT or PE Prevention of DVT or PE in hip and knee replacement surgery patients

Rivaroxaban Dosaging 10mg tablets – prophylactic dose With or without food 15mg tablets – treatment dose With food 20mg tablets – treatment dose

Rivaroxaban Dosage in DVT/PE LMWH is not needed initially 15mg po BID for 3 weeks then 20 mg po QD for the proper length of treatment

Rivaroxaban Dosing for VTE Prevention in Hip and Knee Replacement Hip replacement 10 mg po qd for 35 days Knee replacement 10mg po qd for 12 days

Transition to Other anticoagulants Discontinue warfarin and start rivaroxaban when the INR is below 3. No data on switching from rivaroxaban to warfarin Recommended: discontinue warfarin and start parenteral anitcoagulation and warfarin at the next scheduled dose to avoid periods of inadequate anticoagulation Transitioning to another rapid onset anticoagulant, start at the next scheduled dose

Missed Dose Those taking 15mg twice daily Those taking 20mg once daily Take the missed dose as soon as possible for a total of 30mg a day May double the dose and take 30mg at once to achieve 30mg daily dose Those taking 20mg once daily Take the next dose immediately and continue on a daily dose (every 24 hours) Do not double dose

Laboratory/Monitoring PT is elevated and may be useful in monitoring aPTT is prolonged There is no reliable correlation between elevation of these values and therapeutic effect

Reversal of Rivaroxiban No Antidote or reversal agent Activated Charcoal to reduce absorption Not expected to be dialyzable due to high protein binding Prothrombin Complex Concentrate (PCC) may be considered in severe hemorrhage

Apixaban

Apixaban Factor Xa inhibitor Peak plasma concentration 2-4 hours Half life 5 – 6 hours and 12 hours with repeated dosing No active circulating metabolites Excretion Renal – 27% 25% in urine, biliary and intestinal

Apixaban Containdications Severe hypersensitivity to Apixaban Active, pathalogical bleeding

Apixaban Warnings Not recommended in hemodynamic instability with PE or thrombolysis or embolectomy Not recommended with prosthetic heart valves Not to be used with neuroaxial anesthesia Not to be used with strong inhibitors or inducers of CYP3A4 and P-gp Not to be used with other anticoagulants Category B in pregnancy In animal models, 12% of maternal dose is excreted during lactation

Apixaban Indications Nonvalvular Atrial Fibrillation DVT and PE treatment VTE prophylaxis in hip and knee replacement

Dosage Postoperative prophylaxis DVT/PE Hip – 2.5mg po BID x 35 days Knee – 2.5 mg po BID x 12 days DVT/PE 10mg po BID x 7 days then 5mg po BID

Apixaban Warfarin Conversion Apixaban affects INR If converting from apixaban to warfarin, start Heparin or LMWH at next scheduled dose of apixaban and discontinue LMWH when INR reaches the target range Converting from warfarin to apixaban Start apixaban when the INR is less than 2.

Apixaban Administration Take with or without food May crush tablet If missed dose, take immediately and then every 12 hours there after Do no double dose for missed doses

Medications Contraindicated with Apixaban (9) Carbamazapine Dexamethasone Fosphenytoin Phenytoin Prothrombin Complex Concentrate Rifabutin Rifampin St. John’s Wort Warfarin

Laboratory Abnormalities with Apixaban Increases INR Increases PT Increase aPTT Not reliable for monitoring

Reversal of Apixaban No specific antidote or reversal agent Bleeding effects last 24 hours Due to high plasma protein binding, it is not expected to be dialyzable PCC or recombinant factor VIIa may be considered but no evidence for efficacy Activated charcoal reduces absorption

Edoxaban

Edoxaban Factor Xa inhibitor Plasma availability 62% Half life 10 -14 hours Peak plasma concentration 1 - 2 hours Excretion primarily unchanged in the urine with a minority from the biliary and intestinal system Take with or without food No data on the effect of crushing Do not double dose if missed

Contrindications Edoxaban Active, prolonged bleeding

Warnings Edoxaban Prosthetic heart valves Neuroaxial anesthesia Pregnancy Category C, discontinue with breast feeding No medications are contraindicated Avoid the use of rifampin (strong inducer of P-gp) Avoid the use of concomitant anticoagulants, thrombolytics and antiplatelet agents Coadministration of P-gp inhibitors during treatment for VTE should reduce dose to 30mg Reduce dose in renal insufficiency Not recommended in moderate to severe liver dysfunction/disease

Indications and Dosages Edoxaban Nonvalvular atrial fibrillation Treatment of DVT and PE Parenteral anticoagulation for 5-10 days then Greater than 60kg: 60mg po QD Less than or equal to 60kg: 30 mg po QD Renal impairment with GFR 15-15ml/min: 30mg po QD Not recommended in moderate to severe liver disease

Anticoagulation Transition with Edoxaban Stop warfarin and start edoxaban when the INR is less than or equal to 2.5 Other oral anticoagulants except warfarin, start at the next scheduled dose To parenteral anticoagulants, stop anticoagulant and start edoxaban at the next scheduled dose To warfarin: decrease dose of edoxaban by 50% and start warfarin. Discontinue edoxaban when the INR is >2

Transition of Edoxaban To warfarin: decrease to 30mg a day and start warfarin. Discontinue edoxaban when INR is greater than 2 (if takeing 30mg then decrease to 15mg) Discontinue edoxaban and start parenteral AC and warfarin at the next scheduled dose To another short acting agent: discontinue edoxaban and start new agent at the next scheduled dose

Clinical Pearls and Summary Dabigatran tablet/capsule cannot be altered – significantly increases bioavailability Dabigatran increases the TT and ECT Rivaroxaban in doses of 15mg and 20mg must be taken with food Rivaroxaban can be used as monotherapy without initial use of parenteral anticoagulation PCC may be useful for bleeding complications with rivaroxaban Apixaban is pregnancy category B

Clinical Pearls and Summary Tablet may be crushed for administration with Apixaban 9 medications contraindicated with Apixaban When transitioning edoxaban to warfarin, parenteral anticoagulation may not be needed, may overlap a lower dose of edoxaban with warfarin until the INR is in target range Edoxaban is not approved for VTE prophylaxis in hip and knee replacement surgical patients

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