Novel Anticoagulants

Novel Anticoagulants Mark T. Reding, MD Associate Professor of Medicine Division of Hematology, Oncology, and Transplantation Director, Center for Bleeding and Clotting Disorders University of Minnesota Medical Center American College of Physicians Minnesota Chapter Annual Scientific Session Minneapolis, MN November 8, 2013

Disclosures I have served as an advisory board member, consultant, speaker, and / or received research funding from: Baxter Bayer Biogen Idec Novo Nordisk Octapharma Pfizer (All activities related to hemophilia) Off-label use will be mentioned: dabigatran, rivaroxaban, apixaban

Anticoagulant Therapy What are the options? 1930s heparin 1950s warfarin 1990s low MW heparins 1990s direct thrombin inhibitors 2000s factor Xa inhibitor 2010s new oral anticoagulants More new drugs are coming...

Partial List of Anticoagulant Drugs Under Development Weitz JI et al. Chest 2012

New Oral Anticoagulants Dabigatran Pradaxa (Boehringer Ingelheim) Rivaroxaban Xarelto (Janssen) Edoxaban Lixiana (Daiichi Sankyo) Apixaban Eliquis (Bristol-Myers Squibb / Pfizer) Approved only in Japan, for VTE prophylaxis

New Oral Anticoagulants Approval History Dabigatran Rivaroxaban Apixaban VTE prophylaxis (THA, TKA) Europe Mar 2008 Canada Jun 2008 Europe Sep 2008 Canada Sep 2008 USA July 2011 Europe May 2011 Canada Mar 2012 Atrial fibrillation Canada Oct 2010 USA Oct 2010 Europe Aug 2011 USA Nov 2011 Europe Dec 2011 Canada Jan 2012 Europe Nov 2012 Canada Dec 2012 USA Dec 2012 Europe Dec 2011 VTE treatment Canada Feb 2012 USA Nov 2012 Acute coronary syndromes Europe May 2013

Summary of Major Clinical Trials VTE prophylaxis VTE treatment Atrial fibrillation Acute coronary syndromes REMODEL RECOVER REMOBILIZE RENOVATE REMEDY RESONATE RELY RELYABLE REDEEM RENOVATE 2 RECOVER 2 RECORD 1 RECORD 2 RECORD 3 RECORD 4 EINSTEIN-DVT EINSTEIN-EXT EINSTEIN-PE ROCKET-AF ATLAS (ACS-TIMI 46) ATLAS (ACS-TIMI 51) ADVANCE 1 ADVANCE 2 ADVANCE 3 AMPLIFY AMPLIFY-EXT ARISTOTLE AVERROES APPRAISE 1 APPRAISE 2 Dabigatran Rivaroxaban Apixaban

FDA Approved Indications As of October 2013 Dabigatran Rivaroxaban Apixaban VTE prophylaxis (THA, TKA) x x Atrial fibrillation VTE treatment x x Acute coronary syndromes x x x

Pharmacokinetics Dabigatran Rivaroxaban Apixaban Target Thrombin Factor Xa Factor Xa Peak Effect (h) 2 3 3 4 3 4 Half-life (h) 12 17 5 13 8 15 Dosing Frequency Twice daily Daily* Twice daily Clearance 80% Renal 20% Biliary 66% Renal 33% Biliary 25% Renal 75% Biliary * Despite short half-life, once daily dosing possible due to persistence of anti-xa activity Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33

Drug Interactions Dabigatran interacts with drugs that affect the transporter P-glycoprotein (P-gp) Rivaroxaban and apixaban also interact with P-gp drugs, as well as those that affect the microsomal enzyme CYP3A4 Examples Ketoconazole Rifampicin Cyclosporine Itraconazole Clarithromycin Tacrolimus Amiodarone Protease inhibitors Carbamazepine Verapamil St. John s wort Phenytoin Increased risk of major bleeding seen in studies of all 3 drugs when used with anti-platelet agents Schulman S, Crowther MA. Blood 2012; 119(13):3016-23 Harder S, Graff J. Eur J Clin Pharmacol 2013; 69(9):1617-33

Laboratory Monitoring Dabigatran Rivaroxaban Apixaban PT / INR aptt Increases with dose Very insensitive Increases with dose Not linear, plateaus PT / INR and aptt are both prolonged, but to a varying degree, and depend upon the reagents used Thrombin Time Most sensitive Normal TT = no drug Too sensitive No effect No effect Other Ecarin clotting time is the best assay, but is not widely available Anti-Xa assay can be used, but must be standardized to the drug Anti-Xa assay very similar to LMWH, and may not need to re-calibrate Baumann-Kreuziger LM, et al. J Trauma Acute Care Surg 2012

Summary of Clinical Trials Atrial Fibrillation VTE Prophylaxis VTE Treatment

Summary of Clinical Trials Atrial Fibrillation RE-LY (Connolly SJ et al. NEJM 2009; 361:1139-51) N = 18,113 Dabigatran 150 mg bid vs. warfarin Reduced risk of stroke (1.11% / yr vs. 1.69% / yr) Similar major bleed risk BUT... Warfarin TTR averaged 64% IF... Compare to patients with warfarin TTR > 65% Dabigatran not superior to warfarin Dabigatran associated with less ICH, but double the risk of major GI bleed

Summary of Clinical Trials Atrial Fibrillation ROCKET AF (Patel MR et al. NEJM 2011; 365:883-91) N = 14,264 Rivaroxaban 20 mg daily vs. warfarin Rivaroxaban was non-inferior to warfarin for prevention of stroke No overall difference in major bleeding, however Rivaroxaban associated with less ICH and fatal bleeding, but more GI bleeding

Summary of Clinical Trials Atrial Fibrillation ARISTOTLE (Granger CB et al. NEJM 2011; 365:981-92) N = 18,201 Apixaban 5 mg bid vs. warfarin Apixaban was superior in preventing stroke (1.27% / yr vs. 1.6% / yr), with less overall bleeding (7.7% absolute risk reduction) and lower all cause mortality Apixaban associated with less ICH (0.8% / yr vs. 0.33% / yr) No increase in GI bleeding

Summary of Clinical Trials VTE Prophylaxis (THA, TKA) Dabigatran Rivaroxaban Apixaban vs. Low Molecular Weight Heparin Equal or better efficacy Similar bleeding risk Advantage of oral administration (Dabigatran and apixaban are not approved in the US for this indication)

Summary of Clinical Trials VTE Treatment Dabigatran Rivaroxaban Apixaban vs. Warfarin or Placebo Non-inferior to warfarin, with same or less overall (INR 2.0 3.0) bleeding risk and less major bleeding RE-MEDY = 65% Need to carefully look at TTR for warfarin patients EINSTEIN = 58% Better than placebo (not a surprise) with acceptable bleeding risk EINSTEIN-PE = 63% Apixaban had same bleeding risk AMPLIFY as placebo?!? = 61% Time in Therapeutic Range (Dabigatran and apixaban are not approved in the US for this indication)

Management of Bleeding Dabigatran Rivaroxaban Apixaban Antidote None None None Activated charcoal* Yes Yes Yes Dialysis ~35% protein bound ~60% removed in 2-3 h ** Highly protein bound Dialysis ineffective Highly protein bound Dialysis ineffective * Activated charcoal indicated within 2 3 hours of drug ingestion ** Dabigatran has a very large volume of distribution (60 70 L); expect multiple dialysis sessions to be required

Hemostatic Agent Options for Management of Bleeding Name Category Available in US? Aminocaproic acid antifibrinolytic Yes Tranexamic acid antifibrinolytic Yes Profilnine, Bebulin 3 factor PCC Yes Cofact, Kanokad 4 factor PCC No Octaplex, Kaskadil 4 factor PCC, + PC, PS No Beriplex / Kcentra 4 factor PCC, + PC, PS, AT Yes FEIBA Activated PCC Yes NovoSeven rfviia Yes (None are approved in the US for this indication)

Use of Hemostatic Agents for Management of Bleeding Summary of Data Dabigatran Rivaroxaban Apixaban Animal Human Animal Human Animal Human 3 factor PCC Case rpt +/- 4 factor PCC Rat +/- Rabbits + Mice ICH + In vitro + In vivo - Case rpt - Rats + Rabbits - In vitro +/- In vivo + In vitro + apcc Rats +/- Mice - In vitro + Rat + Primate + In vitro + In vitro + rfviia Rats +/- Mice +/- Mice ICH - In vitro + Case rpt +/- Rat + Rabbits +/- Primate +/- In vitro +/- In vitro + + effective, - not effective, +/- mixed results Bottom Line: very little human, in vivo, real-world, published experience at this time

Use of Factor Concentrates for Management of Bleeding Factor Concentrates are NOT antidotes They create hypercoagulability, not reversal Specific reversal agents in early phase trials Thrombotic risk is present Dabigatran apcc (FEIBA) 50 U/kg Rivaroxaban and Apixaban 4-Factor PCC (Kcentra) 50 U/kg Siegal DM, Crowther MA. Eur Heart J 2013; 34(7):489-498b. Schulman S. HTRS 2013 Annual Meeting, oral presentation. Khoo TL, et al. Int J Lab Hematol 2013; 35(2):222-4. Eerenberg ES et al. Circulation 2011; 124(14):1573-9.

Perioperative Management Drug Dabigatran Rivaroxaban Apixaban Package Insert Recommendations For CrCl >50, stop 1 to 2 days prior For CrCl <50, stop 3 to 5 days prior Consider longer if major surgery, spinal puncture, spinal or epidural catheter Stop at least 24 hours prior Stop at least 48 hours prior (moderate or high risk procedures) Stop at least 24 hours prior (low risk procedures) Lab testing If TT (dabigatran) or anti-xa (rivaroxaban, apixaban) are normal, drug has cleared If not normal, there is still drug on board (but cannot quantitate risk)

New Oral Anticoagulants Advantages Direct anticoagulants Predictable pharmacokinetics No monitoring needed Few diet / drug interactions Disadvantages Cannot monitor Renal / hepatic excretion No antidotes Limited experience Lack of long-term safety data Cost

New Oral Anticoagulants To use or not to use? Atrial Fibrillation Those already on warfarin, with good INR control, have little to gain by switching New agents slightly preferred over warfarin for those newly initiating treatment Some evidence suggests an increased risk of MI or ACS related to dabigatran; use with caution in those with CAD Watch renal / liver function

New Oral Anticoagulants To use or not to use? Prevention of VTE Dabigatran and apixaban are not approved in the US for this indication Rivaroxaban is a good alternative to LMWH / warfarin in this setting Approval currently limited to orthopedic surgery

New Oral Anticoagulants To use or not to use? Treatment of VTE Dabigatran and apixaban are not approved in the US for this indication Rivaroxaban was recently approved in the US for this indication (Nov. 2012) Rivaroxaban is a good choice for those who need short term treatment Long term concerns: safety, cost (to patient), breakthrough clots (?)

Malignancy New Oral Anticoagulants To use or not to use? We need more experience in patients with: Pregnancy Severe thrombophilia (APS, PC, PS, RE-ALIGN AT, double Study heterozygotes or homozygotes for FVL / PGM) Extremes of body weight Impaired renal / hepatic function Mechanical heart valves Those with more than low bleeding risk Real-world compliance (not on studies) (NEJM 2013; 369:1206-14) Dabigatran vs. warfarin Aortic and mitral valves Terminated early due to excess thromboembolic and bleeding events in dabigatran group

Take Home Points The new oral anticoagulants are not necessarily better than warfarin; they are different, and each has advantages and disadvantages Careful patient selection is crucial for the safe use of new oral anticoagulants Management of bleeding complications from the new oral anticoagulants is a major clinical challenge; we lack data and real world clinical experience