Novel Anticoagulants

Novel Anticoagulants Kathleen Ozsvath, MD Associate Professor of Surgery, Albany Medical Center Partner, The Vascular Group, Albany, NY Chief of Vascular Services, Samaritan and St. Mary s Hospital, Troy, NY

Novel Oral Anticoagulants Novel Oral Anticoagulants Dabigatran-Pradaxa Rivaroxaban-Xarelto Apixaban-Eliquis

Categories Vitamin K antagonists Coumarin Heparin and derivativesactivate antithrombin III LMWH Factor Xa inhibitors Fondaparinux- Arixtra Rivaroxaban-Xarelto Apxaban-Eliquis Edoxaban-Savaysa Thrombin inhibitors Hirudin- Lepirudin Bivalirudin Argatoban Dabigatran-Pradaxa Other Batroxobin- Hementin-

Warfarin and its issues Patient compliance issues Narrow therapeutic index Slow onset and offset of action Dietary interactions Drug interactions Need for monitoring Non adherence leads to 30-50% of treatment failures

Pharmacokinetics of NOACs Action Dose Dabigatran (Pradaxa) Direct Thrombin Inhibition 150 mg BID, 75 mg BID for GFR 15-30 ml/min Rivaroxaban Xareltro Activated Factor Xa Inhibitor 20 mg qd 15 mg qd for GFR 15-30 ml/min Apixaban Eliquis t 1/2 12-17 hrs 5-13 hrs 12 hrs Clearance 80% renal 60% renal 35% biliary Metabolism Conjugation to active glucuronides CYP3A4 CYP2J2 Activated Factor Xa Inhibitor 5 mg BID 2.5 mg BID for age>80, wt < 60 kg, Cr >1.5 25% renal 75% biliary CYP3A4 P-GP Interact Yes Yes Minimal

Classes of Direct Thrombin Bivalent (all IV): Hirudin Bivalrudin Lepirudin Desirudin Inhibitors Univalent Discovered 1884 Argatroban (IV) John Berry Haycraft Melagatran (prodrug Ximelagatran-development stopped) Dabigatran (oral)-pradaxa

Dabigatran Xa inhibitors By Joe D (Own work) [GFDL (http://www.gnu.org/copyleft/fdl.html), CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/) or CC-BY-SA-2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/2.5-2.0-1.0)], via Wikimedia Commons

What does thrombin do? Forms a clot, and then stabilizes it Stimulates the generation of more thrombin Inhibits fibrinolysis by stimulating thrombus activated fibrinolysis inhibitor (TAFI) Activates platelets

What does Factor Xa do? Trypsin-like serine protease Links the intrinsic and extrinsic pathways Converts prothrombin to thrombin

What is Dabigatran approved for? United States: Prevention of stroke in patients with non-valvular atrial fibrillation Treatment of VTE (April 2014) and extended treatment to prevent recurrent VTE Europe and Canada: Prevention of thromboembolic disease following hip or knee replacement surgery Non-valvular atrial fibrillation

What are Factor Xa Inhibitors approved for? Apixiban: Atrial Fibrillation VTE prophylaxis New drug application submitted for VTE treatment Rivaroxaban: DVT/PE treatment VTE prophylaxis Atrial fibrillation

Dabigatran Clinical Trials DVT prophylaxis: 2005: BISTRO II-Europe, South Africa 2007: RE-NOVATE, RE-MODEL-Europe, Australia, South Africa 2008: RE-MOBILIZE-US, Canada, Mexico, UK Atrial Fibrillation: 2007: PETRO-Europe, US 2009-ongoing: RE-LY-44 countries Venous Thrombosis: 2009: RECOVER 2011: RECOVER II, RESONATE, REMEDY Acute and Post-coronary syndromes and post-mi: 2009: REDEEM

Major Clinical Trials: Dabigatran DVT prophylaxis (all double blind) Dabigatran v. Enoxaparin RENOVATE 220 D 220 mg qd v. E 40 mg x 28-35 d RENOVATE 150 D 150 mg qd v. E 40 mg x 28-35 d RENOVATE II D 220 mg qd v. E 40 mg x 28-35 d REMODEL 220 D 220 mg qd v. E 40 mg x 6-10d REMODEL 150 D 150 mg qd v. E 40 mg x 6-10d Dosing* Indication** VTE Major Bleeds REMOBILIZE 220 D 220 mg qd v. E 30 mg BID x 12-15d THR D: 6.0% E: 6.7% THR D: 8.5% E: 6.7% THR D: 7.7% E: 8.8% TKR D: 36.4% E: 37.7% TKR D: 40.5% E: 37.7% D: 1.3% E: 2.0% D: 1.6% E: 2.0% European dosing regimen: Noninferior to Enoxaparin TKR D: 31% E: 25% US dosing regimen: Inferior to Enoxaparin REMOBILIZE 150 D150mg qd v. E 30 mg BID x 12-15d TKR D: 34% E: 25% D: 1.4% E: 0.9% D: 1.5% E: 1.3% D: 1.3% E: 1.3% D: 1.5% E: 1.3% D: 0.6% E: 1.4% *D=Dabigatran, E=Enoxaparin ** Total hip replacement=thr, total knee replacement=tkr

Major Clinical Trials: Dabigatran VTE treatment (all double blind) Trial Dosing* Indication Recurrent VTE RECOVER II** (not fully published) D 150mg BID v. W INR 2.0-3.0 for 6 months RESONATE D 150 mg BID v. PLACEBO Acute proximal DVT/PE Secondary prevention after 6-18 mos treatment of VTE D: 2.4% W: 2.2% D: 0.4% P: 5.6% Major Bleeds* RECOVER** D 150mg BID v. Acute proximal D: 2.4% D: 1.6% Noninferior, equal major bleeds, fewer minor bleeds, more W INR 2.0-3.0 for 6 DVT/PE W: 2.1% W: 1.9% months dyspepsia and drug discontinuation D: 1.2% W: 1.6% D: 0.3% P: 0.0% Equal to warfarin, with less major or clinically relevant REMEDY D 150mg BID v. Secondary prevention D: 1.8% D: 0.9% bleeding, more W INR effective 2.0-3.0 for than after 3-12 placebo, mos W: but 1.3% higher W: 1.8% risk than 6-36 mos treatment of VTE placebo *D=Dabigatran, W=Warfarin, P=Placebo ** After initial parenteral anticoagulation

Factor Xa Trials Trial Dosing* Indication Recurrent VTE EINSTEIN R 15mg BID x 3 wks then 20 qd v. W INR 2.0-3.0 EINSTEIN-PE R 15mg BID x 3 wks then 20 qd v. W INR 2.0-3.0 EINSTEIN- EXTEND AMPLIFY-EXT R 20mg daily v. PLACEBO A 2.5 mg or 5.0mg BID v. PLACEBO Acute proximal DVT R: 2.1% W: 3.0% PE R: 2.1% W: 1.8% Secondary prevention after 6-12 mos treatment of VTE Secondary prevention after 6-12 mos treatment of VTE R: 1.3% P: 7.1% A(2.5): 1.7% A(5.0): 1.7% P: 8.8% Major Bleeds* R: 0.8% W: 1.2% R: 1.1% W: 2.2% R: 0.7% P: 0.0% A(2.5): 0.2% A(5.0): 0.1% P: 0.5%% R=Rivaroxaban, A= Apixaban, W=Warfarin, P=Placebo

Factor Xa Clinical Trials DVT prophylaxis: 2008: RECORD 1,2,3 (Rivaroxaban knee, hip, hip) 2008-10: ADVANCE 1,2,3 (Apixaban knee, knee, hip) Atrial Fibrillation: 2011: ROCKET-AF (Rivaroxaban) 2011: ARISTOTLE (Apixiban) Venous Thrombosis (DVT/PE): 2010: EINSTEIN (Rivaroxaban) 2012: EINSTEIN-PE (Rivaroxaban) 2013: EINSTEIN-EXTEND (Rivaroxaban) AMPLIFY (Apixiban) AMPLIFY-EXT (Apixiban) Superior, fewer bleeds (knees) Superior, with European Dosing, inferior with US Noninferior, fewer dosing fatal bleeds Superior, fewer bleeds, death Noninferior Noninferior, fewer bleeds in PE trial Superior, more bleeds than placebo Noninferior, fewer bleeds Superior, more bleeds than placebo

Atrial Fibrillation Post-approval monitoring for Dabigatran: 1.6 bleeding events per 100,000 days risk: NEJM 2013:368:14-15 AHA/ACC Guidelines for Stroke prophylaxis for atrial fibrillation:» Warfarin Class I A» Dabigatran Class IB» Rivaroxaban Class IIb B» Apixaban Class IB

Dabigatran and Atrial Fibrillation RE-LY Trial: NEJM 2009:361:1139-51. Stroke prevention 18,113 patients at a > 2.5% per year estimated risk for CVA (CHADS 2 score) randomized to warfarin (INR goal 2-3) v. Dabigatran 110 BID or 150 BID Dabigatran 150 BID dosing 1.53% per year risk of CVA or embolism compared to 1.6% per year for warfarin (CI 0.74-1.11, p<0.001 for non-inferiority) Major bleeding 3.11% v. 3.36% (p=0.31), Mortality equivalent Hemorrhagic stroke 0.10% v. 0.38% (p<0.01) Contraindicated in patients with prosthetic heart valves

Atrial Fibrillation Trials Trial Dosing* Indication Primary endpoints RELY Superior (RR 0.66, p<0.001, equal major bleeds) ROCKET-AF D 150mg BID D 110mg BID W INR 2.0-3.0 (67% TTR) R 20mg qd W INR 2.0-3.0 (57.8% TTR) Acute proximal DVT D: 1.1% W: 1.7% PE R: 1.7% W: 2.2% Major Bleeds D: 3.3% W: 3.6% Non-inferior (HR 0.79, p<0.001, equal major bleeds) ARISTOTLE A 5mg BID W INR 2.0-3.0 (TTR 66%) Secondary prevention after 6-12 mos treatment of VTE A: 1.3% W :1.6% R: 5.6% W: 5.4% R: 2.1% W: 3.1% Superior (HR 0.79, p=0.01, fewer major bleeds) Time Therapeutic Range = TTR

Drawbacks to NOACs Cost: about $250 per month (no insurance) or copays of $20-50/month. No antidote Some drug interactions Long term (> 2years safety unknown) GI upset (some contain tartaric acid, to lower ph for adequate absorption-this can cause dyspepsia) Concomitant use of antiplatelet agents increases risk of bleeding two-fold Possibly higher risk of MI with Thrombin Inhibitors compared to Factor Xa inhibitors (Ann Intern Med: 2012;157(11):796-807)

Black Box Warnings Factor Xa inhibitors-increased risk of stroke after discontinuation for nonvalvular atrial fibrillation HR of 1.5 compared to warfarin for rivaroxaban, p=0.026 Need to bridge when converting to warfarin Rivaroxaban-Epidural or spinal hematoma with use of epidurals, spinal puncture (hold rivaroxaban >18 hrs prior to pulling, and wait 6 hrs before resuming) Dabigatran-increased risk of acute coronary events (absolute risk MI/ACS 0.27%, relative risk 33%)

Effects on Coagulation Tests PT: increase or no change (not reliable) aptt: reliably increased. >80 sec at trough associated with increased risk of bleeding in afib pts Thrombin clotting time (TCT): increased (impractical-2 day turn around in many labs)

Management of anti-coagulant associated bleeding: HASHTI Hold further dose of Anticoagulant Consider Antidote Supportive treatment Local or Surgical Hemostatic measures Transfusion Investigate Source of Bleeding

Potential antidotes FFP-No clinical data, but decreased vol of intracerebral hemorrhage in mice with dabigatran Prothrombin Complex Concentrates (PCC): 3 Factor-II, IX, X, Prot C and S; 4 Factor- II, VII, IX, X, Prot C and S. Some minimal data in healthy subjects and animals Activated PCC: contains factors II, VII, IX and X, activated during manufacturing. Possible reversal in animal models Activated Charcoal-99.9% absorption of dabigatran if given within 2 hours of ingestion Recombinant Factor VIIa-developed for hemophiliacs-in develpment Hemodialysis-may not be feasible if patient is hemodynamically unstable

Drug Interactions-Dabigatran Drug Amiodarone +12-60% Atorvastatin +18% Clarithromycin,erythromycin +15-20% Dronedarone +70-100% Ketoconazole +140-150% Quinadine +50% Rifampin, phenytoin, St John s Wort, phenobarbital, carbamezepim % increase or decrease in serum concentration -66% Verapamil +12-+180%

Drug Interactions-Rivaroxaban Drug Strong P-gp Inducers and CYP3A4 Inducers: Rifampin, phenytoin, St John s Wort, phenobarbital, Strong CYP3A4 Inhibitors and P-gp Inhibitors: Ketoconazole, Itraconazole Clarithromycin,erythromycin Fluconazole Recommendation Avoid use together Avoid use together Increases anticoagulant effect Increases anticoagulant effect

Drug Interactions-Apixaban Drug Strong P-gp Inducers and CYP3A4 Inducers: Rifampin, phenytoin, St John s Wort, phenobarbital, Strong CYP3A4 Inhibitors and P-gp Inhibitors: Ketoconazole, Itraconazole Clarithromycin,erythromycin Recommendation Avoid use together Reduce dose to 2.5mg BID Reduce dose to 2.5mg BID

Recommended Labs to follow All patients, annually: hemoglobin, renal and liver function panels CrCl 30-60 ml/min or if >75 years old: renal function every 6 months CrCl 15-30 ml/min: renal function every 3 months (contraindication for use of dabigatran) On an indication basis: recheck labs if a condition occurs that may change renal or hepatic function

Summary Novel anticoagulants provide a welcome alternative to warfarin based on ease of use, safety, and efficacy FDA approval for some venous indications is still pending Head to head trials would be needed to determine superiority/inferiority in treating and preventing VTE comparing Factor Xa and thrombin inhibitors (might be difficult-who is going to pay for these trials? Registries may help?) The first drug that has a reversal agent will gain significant advantage in the market of anticoagulants