Novel anticoagulants: How to make a choice? Prof. dr. Hugo ten Cate Maastricht University Medical Center Contents • Anticoagulant treatment in ACS (as a typical atherothrombotic disease) • Involvement of coagulation proteins in atherosclerosis • Pleiotropy of thrombin in atherosclerosis/thrombosis • Therapeutic vascular “spinoff” effects of NOACs? Indications (N)OACs • (Secondary) prevention of venous thromboembolism (VTE) • Prevention of embolic stroke in atrial fibrillation (AF) • Secondary prevention of coronary events in Acute Coronary Syndrome (ACS)? “Old Old”” versus new Synthetic oral anticoagulants rivaroxaban apixaban dabigatran Indications for NOACs • Registered for VTE and AF; practical difficulties remain (patient selection, renal function, compliance, how to manage in practice, how to handle bleeding etc) • In ACS there is controversy: does anticoagulation on top of platelet inhibition (background of atherosclerosis) make sense Arterial and Venous Thrombosis Mackman N. Nature. 2008 Thrombosis occurs by interaction of three elements AF, VTE CAD Atherothrombosis • Considered a platelet dependent problem • Dual/triple APT current cornerstone of secondary antithrombotic prevention; bleeding complications limit the extent of effectiveness (eg triple therapy, TRA) • How about anticoagulation? Long-term anticoagulation in patients with coronary disease, and future developments. Verheugt, Freek Current Opinion in Cardiology. 23(4):315-319, July 2008. DOI: 10.1097/HCO.0b013e3283021aef Figure 1 Meta-analysis of trials of oral anticoagulants and aspirin versus aspirin alone with a mean INR under 2.0 2 Long-term anticoagulation in patients with coronary disease, and future developments. Verheugt, Freek Current Opinion in Cardiology. 23(4):315-319, July 2008. DOI: 10.1097/HCO.0b013e3283021aef Figure 2 Meta-analysis of trials of oral anticoagulants and aspirin versus aspirin alone with a mean INR over 2.0 3 Long-term anticoagulation in patients with coronary disease, and future developments. Verheugt, Freek Current Opinion in Cardiology. 23(4):315-319, July 2008. DOI: 10.1097/HCO.0b013e3283021aef Table 1 Trials with novel oral anticoagulants in ischemic heart disease 4 Median D-dimer concentration over time. Oldgren J et al. Eur Heart J 2011;32:2781-2789 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: [email protected] Kaplan–Meier curve depicting the primary endpoint, i.e. the composite of major and clinically relevant minor bleeding. Oldgren J et al. Eur Heart J 2011;32:2781-2789 Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: [email protected] Alexander et al, NEJM 2011 Mega et al, NEJM 2012 So how about these (N)OACs? NOACs in ACS • VKA and one NOAC, combined with APT, effective in reducing CV death (in all cases at the cost of bleeding) • Is this purely prevention of (athero)thrombosis? • Or are there other effects? Is the level of thrombin generated in blood clinically relevant? Atherosclerotic Plaque Progression Thrombus age after thrombosuction: proportions of treated patients (n=199). Rittersma S Z et al. Circulation 2005;111:1160-1165 Copyright © American Heart Association Histological spectrum of thrombus and atherosclerotic plaque tissue retrieved by intracoronary thrombectomy. Rittersma S Z et al. Circulation 2005;111:1160-1165 Copyright © American Heart Association IF STAININGS – CO-LOCALIZATION OF TF, FVII & FX Borissoff et al, Circulation. 2010 24;122(8):821-30 EARLY ATHEROSCLEROSIS EXHIBITS AN ENHANCED PRO-COAGULANT STATE Borissoff et al, Circulation. 2010 Aug 24;122(8):821-30 SIGNIFICANTLY HIGHER ETP & TAT IN EARLY ATHEROSCLEROTIC LESIONS Borissoff et al, Circulation. 2010 Aug 24;122(8):821-30 “What is all that thrombin for?” Ken Mann Elements of blood coagulation Vessel Wall Injury Collagen Tissue Factor Platelet Activation Thrombin Primary Thrombus Fibrin Stable Thrombus 29 Elements of blood coagulation Extrinsic Pathway Intrinsic Pathway HMWK Prekallikrein Kallikrein Ca FXII TF 2+ FVII FXIIa TF.FVII HMWK FIX FXI FXIa FVIII - TFPI TF.FVIIa FIXa FVIIIa PL, Ca 2+ FX EPCR Thrombomodulin - Thrombin APC Protein C APC FXa FVa Prothrombin PL, Ca FV 2+ Thrombin Fibrinogen T-PA PAI-1 Fibrin FXIII FXIIIa Plasminogen Plasmin Common Pathway Cross -linked Fibrin Fibrin Degradation Produc ts Fibrinolysis 30 PHENOTYPIC MODULATION OF THE ARTERIAL VESSEL WALL: NON-HEMOSTATIC ACTIONS OF KEY COAGULATION PROTEINS Borrisoff, Spronk & ten Cate, NEJM 2011 Thrombin and atherosclerosis: causality? • Is thrombin (generation) a driver of atherosclerosis and atherothrombosis? Thrombin-induced Atherogenesis? Borissoff et al, Cardiovasc Res 2009 ;82(3):392-403 Thrombin being proatherogenic? Borissoff, Joossen et al, JACC Cardvasc Imaging 2012 in press EXTENSIVE ATHEROSCLEROSIS IN TM Pro/Pro / ApoE-/- CAROTID ARTERIES p<0.0001 p<0.0001 p<0.0001 p=0.0021 p<0.0001 p<0.0001 p=0.0355 p=0.0052 p=0.0001 INCREASED ACCUMULATION OF MФ AND LESS α-ACTIN AND COLLAGEN I/III IN TM Pro/Pro / ApoE-/- p<0.0001 p=0.0029 p=0.0002 p=0.0058 p=0.0002 P=0.0039 INTRAPLAQUE HEMORRHAGE & PLAQUE RUPTURE IN TM Pro/Pro / ApoE-/- MICE Black Arrows – Micro-clots within a plaque Red Arrows – Organized thrombus Black Arrows – Organized thrombi Secondary prevention • New anticoagulants? • Preventing atherosclerosis? • Limit I/R injury of the heart with anticoagulants? DABIGATRAN/APC PROTECTS AGAINST SEVERE ATHEROSCLEROSIS PROGRESSION IN TM Pro/Pro / ApoE-/- Borissoff et al, submitted Results AOI I/R injury : Evans Blue/TTC staining AAR (Red) AOI (White) Placebo 2 hrs R AOI (as % of AAR) NIA (Blue) 50 Placebo APC 40 30 * 20 * ## ** ### *** 10 0 *** 2 6 24 Reperfusion time (hrs) AOI APC 2 hrs R APC 24 hrs R AOI (as % of AAR) 6 hrs R 40 30 20 * 10 0 Loubele et al, ATVB 2009 Placebo APC Heparin *,# p<0.05 Antithrombotic therapy 2015 Add low dose DTI, DXaI?