Update on Oral Anticoagulants Dr. Miten R. Patel Cancer Specialists of North Florida Cell 904-451-9820 Email miten.patel@csnf.us
Overview Highlights of the 4 new approved oral anticoagulants Results from major trials for VTE Antidotes Take home points
What's Wrong With Coumadin? Narrow therapeutic range Slow onset of action Slow offset of action (long duration of action, long elimination half life) Multiple drug interactions and dietary restrictions Monitoring required to maintain in therapeutic range Difficult to manage for invasive procedures Impaired quality of life for the patient Labor intensive for health care provider
The Ideal Anticoagulant Oral administration Rapid onset of action/rapid offset of action Wide therapeutic range Predictable therapeutic effect with fixed or weight-based dosing No food or drug-drug interactions No monitoring required (but the ability to monitor if desired) Well defined pharmacokinetics Easily reversible Cost effective
The Next Generation (DOACs) Direct thrombin (IIa) inhibitor Dabigatran (Pradaxa) Factor Xa inhibitors Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa)
Pradaxa Basics Direct thrombin (factor IIa) inhibitor Max anticoag activity 2-3 hours after ingestion Half life 7.1-17 hours Elimination--renal (80%), remainder excreted in bile Contraindicated in patients with CrCl <30ml/min Main side effect--dyspepsia (10%) and bleeding
Pradaxa (Dabigatran) Dosing 150 mg po bid for A Fib 150 mg po bid after 5-7 days of parenteral anticoagulant for VTE Potential for drug-drug interaction with P-gp inhibitors (may need to reduce dose of Pradaxa).
Xarelto Basics Direct factor Xa inhibitor Peak plasma concentration 2.5-4 hours after administration Half life--3.2-9.1 hours Elimination--1/3 renal, 2/3 fecal
Xarelto Dosing DVT/PE- 15 mg po bid for 3 weeks and then 20 mg po daily Non Valvular Afib- 20 mg po daily Reduction in the risk of DVT/PE- 20 mg po daily Post operative DVT prophylaxis for Knee and Hip replacement- 10 mg po daily
Eliquis (Apixaban) Basics Direct factor Xa inhibitor Time to peak AC effect 3-3.5 hours Half life--8-15 hours Elimination--25% renal, 75% fecal Drug-drug interactions Likely CYP3A4 interactions, azoles and mycins
Eliquis Dosing Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Oral: 5 mg twice daily DVT/PE- 10 mg po bid for 7 days followed by 5 mg po twice daily. Hip replacement surgery: 2.5 mg twice daily beginning 12 to 24 hours postoperatively; duration: 35 days Knee replacement surgery: 2.5 mg twice daily beginning 12 to 24 hours postoperatively; duration: 12 days
Renal Dysfunction for Eliquis DVT/PE- no dose adjustments as per prescribing information. However patients with a Creatinine greater than 2.5 were excluded from trials Nonvalvular A Fib- For patients with at least 2 of 3: Creat > 1.5, and or age >80 or weight <60kg, reduce dose to 2.5 mg po bid ESRD- on HD dose is 5 mg po bid. Reduce dose to 2.5 mg po bid if age >80 and weight less than 60 Kg
Edoxaban, Savaysa (Edoxaban) Basics Selective factor Xa inhibitor, inhibits free factor Xa and prothrombinase activity and inhibits thrombin-induced platelet aggregation. Inhibition of factor Xa in the coagulation cascade reduces thrombin generation and thrombus formation. Peak effect is 1-2 hours; half life is 10-14 hours 33 % renal clearance
Savaysa ( Edoxaban) Dosing DVT/PE- Oral: 60 mg once daily after 5 to 10 days of initial therapy with a parenteral anticoagulant <60 Kg 30mg daily On P-gp inhibitor (verapamil/quinidine, azithro, clarithro, eythromycin, keto or itraconazole) Non Valvular A Fib- 60 mg po daily
Drug Warfarin Comparison Pradaxa Xarelto Eliquis Edoxaban Target Vit K epoxide reductase Factor II (Thrombin) Factor Xa Factor Xa Factor Xa Half Life( hours) 40 7-17 3-9 8-15 10-14 hours Monitoring INR Not needed Not needed Not needed Not needed Administration Once daily Once or twice daily Once or twice daily Twice daily Daily Metabolism CYP 450 80 % renal 33 % renal, rest fecal 25 % renal, rest fecal 33 % renal Assay INR Ecarin clotting time? Thrombin time Antifactor Xa, Antifactor Xa N/A Antidote Vit K/FFP Praxbind Recombinant Factor Xa inhibitors (in the works), APCC Recombinant Factor Xa inhibitors (in the works), APCC Recombinant Factor Xa inhibitors (in the works), APCC
Cost Drug Cost/month Warfarin $ 20 Pradaxa $ 300 Xarelto $ 300 Eliquis $ 300 Edoxaban $ 350
VTE Treatment Studies- Xarelto EINSTEIN Study Symptomatic DVT/PE Rivaroxaban 15 mg BID x 3 weeks, followed by 20 mg daily vs. Enoxaparin followed by VKA (Coumadin) Continued treatment arm: rivaroxaban vs. placebo for an additional 6-12 months Non-inferior compared to VKA for recurrent VTE; Superior to placebo for continuation arm No difference in bleeding
Primary Outcome
Other Pivotal Trials RE-COVER (Pradaxa vs. warfarin) n= 2564 Noninferior (2.7% vs. 2.5%) No difference in major bleeding risk AMPLIFY trial Eliquis vs. Warfarin (n= 5395) Noninferior for recurrent VTE (2.3% vs. 2.7%) Noninferior for all cause mortality Lower bleeding risk (RR 0.44) Edoxaban noninferior to warfarin (n= 8292) Primary endpoint recurrent VTE (3.2% vs. 3.5%) No increase in bleeding risk
Cancer Patients Standard of care for patients with active cancer is low molecular weight heparin Retrospective evaluation of the EINSTEIN DVT/PE study shows that Xarelto is superior to Coumadin in patients with active cancer Vedovati et al. - Meta analysis of 6 studies, which encompassed 1132 patients. Rate of VTE with Coumadin was 6 % compared to 3.9 % with newer anticoagulants. Lower rate of bleeding. No head to head comparison with low molecular weight heparin
Consider Warfarin or Heparin/LMWH Mechanical valve Pregnancy (not warfarin!) Heparin Induced Thrombocytopenia however there is a clinical trial ongoing of Xarelto in this setting Anti Phospholipid Syndrome Concomitant use of thrombolytic therapy Valvular afib limited data Renal impairment GI disease/bleeding risk Compliance and Cost
Idarucizumab (Praxbind) RE-VERSE AD study Monoclonal antibody fragment binds Pradaxa with 350 times the affinity with which Pradaxa binds thrombin The reversal agent was granted FDA approval 10/16/2015. Dosing 5gm IV, 2 50 ml bolus infusions Based on NEJM 2015 373:511 90 patients analyzed (51-bleeding, 39- urgent surgery) the agent normalized thrombin time or ECT (ecarin clotting time) within minutes after administration 1 patient in whom anticoagulation had not be re-initiated ended up with thrombotic event within 72 hours 47 minute half life Cost about $3500 / dose wholesale
PCC Factors II, VII, IX and X +Prot C & S Data lacking on efficacy in bleeding patients Data from non-bleeding volunteers where PCC corrected impaired thrombin generation Rabbit hemorrhagic model, 4 factor PCC did not reverse Xarelto induced bleeding Only recommended for imminent risk of death or consideration for major bleeding Dose of 50 units/kg Cost = around $10,000 for a 5000 unit dose.
Andexanet Alpha (andexanet) Recombinant modified human factor Xa decoy protein Retains ability to bind factor Xa inhibitors in the active site with a high affinity Half life is 1 hour Administered as a bolus plus a 2 hour infusion to extend action of drug throughout the duration of infusion
Efficacy Against Factor Xa Inhibitors Andexanet Alfa Orphan drug designation for serious uncontrolled bleeding events who require emergent surgery NEJM March 5, 2016 373:25 Eliquis patients - Anexanet reduced anti-factor Xa activity by 94% (n=24) versus placebo 21% reduction (n=9) (P<0.001). Thrombin generation was fully restored in 100% vs 11% (p<0.001) within 2-5 mins. Xarelto patients anti-factor Xa activity reduced by 92% (n=27) versus 18% (n=14), (P<0.001); Thrombin generation restored in 96% versus 7% (P<0.001) No serious adverse or thrombotic events reported
Take Home Points DOACs are generally safer, lower bleeding risk, lower mortality Meta-analysis VTE (38,000 patients) Fatal bleeding less frequent with DOACs versus vitamin K antagonist treated patients (RR 0.51) All cause mortality lower (RR 0.38) Afib Meta-analysis (27,000 patients) 30 day mortality lower with Pradaxa than warfarin (9.1 vs. 13.0), shorter ICU stays (1.6 versus 2.6 nights)
Take Home Points DOACs are more convenient Less frequent monitoring No routine coagulation monitoring baseline labs and kidney function monitoring for those with borderline/at risk function Holding prior to procedures/surgery (nl kidney) Xarelto 1 day, Savaysa 1 day, Eliquis 2 days, Pradaxa 1 day for minor, 2 days for major. Bridging usually not needed due to quick onset of action.
Take Home Points Resuming after surgery Low bleeding risk, resume 24 hours after High bleeding risk, resume 48-72 hours after procedure Antidotes For pradaxa, available; for the direct Xa inhibitors, expected to come to the market sometime this year.
Questions???
Contact info: Miten R. Patel, MD miten.patel@csnf.us Cell 904-451-9820 Office 904-516-3737