Disclosures. Overview. Anticoagulation in 2015: Where We Are and Where We Are Going. Impact of NOACs in Canada

Transcription

1 Anticoagulation in 2015: Where We Are and Where We Are Going Jeffrey I Weitz, MD, FRCP(C), FACP Professor of Medicine and Biochemistry McMaster University Canada Research Chair in Thrombosis Heart & Stroke Foundation/ J.F. Mustard Chair in Cardiovascular Research Disclosures Grants/Research Support: CIHR, HSF, CFI, ORF Consultant: Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Bayer, Janssen, Portola, Merck, ISIS Overview Status of NOACs in 2015 Reversal agents for NOACs New opportunities New directions Licensed Indications for NOACs in the United States Indication Licensed Agents VTE prophylaxis Rivaroxaban and apixaban VTE treatment Dabigatran, rivaroxaban, apixaban and edoxaban Stroke prevention Dabigatran, rivaroxaban, in AF apixaban and edoxaban Impact of NOACs in Canada Yearly Oral Anticoagulant Prescriptions in Canada from 2008 to 2013 Number of prescriptions for oral anticoagulants increasing each year Prescriptions for NOACs have overtaken those for warfarin amongst cardiologists and neurologists Prescriptions for NOACs are linked to reimbursement Total OAC 4,805,051 5,406,238 5,669,513 6,208,837 6,609,487 7,021,317 Source: IMS Health Canada Inc. (Brogan) Canadian Compuscript 1

2 Oral Anticoagulant Prescriptions in Canada by Specialty in 2013 Impact of Reimbursement on Oral Anticoagulant Prescriptions in Canada dabigatran (CDR) rivaroxaban (CDR) apixaban (CDR) Total OAC 445,657 5,262, , ,185 14,778 6,924 6,114,861 Source: IMS Health Canada Inc. (Brogan) Canadian Compuscript Physician Specialty Report Perceived Need for Reversal Agents for NOACs Some physicians reluctant to prescribe NOACs because of fear of uncontrollable bleeding in the absence of antidotes Patients often have similar concerns Negative press releases Accessed February 23, 2015 Perceived Need for Reversal Agents for NOACs Risk of intracranial bleeding 50% lower with NOACs than with warfarin Outcome of patients with intracranial bleeds no worse with NOACs than with warfarin Outcome of patients with major bleeds in extracranial sites no worse with NOACs than with warfarin Reversal Agents for NOACs Idarucizumab Andexanet Aripazine Structure Humanized Fab Recombinant Synthetic small fragment factor Xa molecule variant Target Dabigatran Factor Xa Universal inhibitors Mechanism Binds dabigatran Competes with Non-covalent with high affinity factor Xa for hydrogen binding inhibitor binding Status Phase III study Phase III study Phase III study well underway started not yet started Ruff, Lancet 2014; Hart, Stroke 2012; Hylek, Eur Heart J 2014; Majeed, Circulation

3 Idarucizumab: Phase II Data with Dabigatranreversal Andexanet Alfa: Phase II Data with Apixaban Anti-fXa Activity End of Bolus 400 End of Infusion Anti-fXa (ng/ml) Placebo (Cohorts 1-3, n=9) 800 mg bolus mg infusion (n=6) Time after bolus (hr) Glund S et al. Presented at AHA, November 2013; Abstract Crowther, M.A., et al. Blood 2013(abstract) Aripazine: Phase II Data with Edoxaban New Indicators for NOACs Indication Trial Treatment No. of Patients Stroke of NAVIGATE-ESUS Rivaroxaban or 7000 unknown source NCT aspirin RESPECT-ESUS Dabigatran or 6000 NCT aspirin Heart failure COMMADER-HF Rivaroxaban or 5000 NCT placebo CAD or PAD COMPASS Rivaroxaban, 24,000 NCT rivaroxaban plus aspirin, or aspirin Ansell JE, et al. N Engl J Med 2014 CAD, coronary artery disease; PAD, peripheral artery disease; VTE, venous thromboembolism NOACs in Existing Indications Indication Trial Treatment No. of Patients Thromboprophylaxis Medically ill MARINER Rivaroxaban or 8000 NCT placebo Cancer patients AVERT Apixaban or placebo 574 NCT Cancer-associated Hokusai-VTE- Edoxaban or 1000 VTE cancer dalteparin NCT Secondary VTE EINSTEIN-Choice Rivaroxaban (20 or 2850 prevention NCT mg) or aspirin AF and ACS PIONEER AF-PCI Rivaroxaban plus ADP 2100 NCT receptor antagonist with or without aspirin or warfarin plus DAPT REDUAL-PCI Dabigatran with NCT clopidogrel or ticagrelor or warfarin plus DAPT New Targets Intrinsic pathway FXII FXI FIX ACS, acute coronary syndrome; AF, atrial fibrillation; VTE, venous thromboembolism 3

4 Why Do We Need New Targets? Holy grail of anticoagulant therapy is to attenuate thrombosis without increasing the risk of bleeding Less intracranial bleeding with NOACs, but annual rates of major bleeding remain at 3% in the AF population Why the Focus on the Intrinsic Pathway? New initiators of the intrinsic pathway identified Attenuated thrombosis in mice deficient in FXII or FXI Minimal alteration in hemostasis; at least with FXII or FXI-directed therapies New Initiators of the Intrinsic Pathway Potential Role of the Intrinsic Pathway in Thrombosis Leukocytes Activated/damaged cells Platelets Medical Devices Ischemic Stroke Venous Thrombosis NETs DNA/histones RNA Inorganic polyphosphates NETs, RNA, poly P NETs, DNA, Poly P Activate FXII Promote FXI activation FXII activation Thrombosis Thrombosis Attenuated Thrombosis in Mice Deficient in FXII or FIX Ischemic Stroke is Attenuated in Mice Deficient in FXII Renne T, J Exp Med 2005;202: Kleinschnitz C J Exp Med 2006; 203:

5 New Drugs that Target the Intrinsic Pathway Like Heparin, a FXIIa-directed Antibody Inhibits Thrombosis in a Rabbit ECMO System Target Drug Polyphosphates Dendrimers, PdSP15, DNase FXII ASOs, Antibodies, Aptamers FXI ASOs, Antibodies, Aptamers, small molecules FIX Pegnivacogin Larsson M et al, Sci Transl Med 2014;6:222ra17 FXI-directed Antibody Attenuates Thrombosis in a Baboon AV Shunt Model Comparison of the Effects of FXII, FXI or FVII Knockdown on Catheter Thrombosis in Rabbits Tucker et al. Blood 2009;113: Yau J et al. Blood in press Phase II Trial Comparing FXI ASO with Enoxaparin for Thromboprophylaxis Comparison of the Efficacy and Safety of FXI ASO and Enoxaparin Elective TKR Enoxaparin (40 mg OD starting after surgery) ASO (200 or 300 mg starting 35 d prior to surgery) FXI ASO, 200 mg FXI ASO, 300 mg Enoxaparin n=144 n = 77 n=72 VTE 27% 4% 30% Major or non- 3% 3% 8% major bleeding Buller, N Engl J Med, 2015 Buller, N Engl J Med,

6 Potential New Indications Prevention of medical device-associated thrombosis (e.g., mechanical heart valves) Prevention or treatment of thrombosis in patients at high risk for bleeding (e.g., ischemic stroke, ESRD) Safer platform therapy in patients receiving dual antiplatelet therapy Conclusions NOACs are slowly replacing warfarin for many indications Introduction of reversal agents and identification of new or expanded indications will increase uptake of NOACs Identification of new therapeutic targets, particularly factor XI, sets the stage for safer antithrombotic therapy 6