Direct oral anticoagulants in daily care: what do we know today and what are the remaining issues?

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CONCLUSIONS Systematic reviews and meta-analyses have shown that DOACS compared with VKAs: in patients with AF, reduced the absolute risk of stroke and of major bleeding in patients with VTE, had a similar risk of recurrence, with a lower risk for bleeding There is a need for further studies There is a need for real world data 2

WHAT DO WE KNOW TODAY AND WHAT ARE THE REMAINING ISSUES? In patients with: Atrial fibrillation venous thromboembolism In at-risk clinical settings: Bleeding Urgent surgery or invasive procedure 3

WHICH ANTITHROMBOTIC STRATEGY FOLLOWING PCI IN PATIENTS ON OAC? Patients with AF undergoing PCI have a high risk of CV events and mortality Dual antiplatelet therapy (DAPT) is the standard management strategy in patients after ACS events and/or PCI Triple therapy (OAC + DAPT) increases bleeding risk in patients on OAC Triple therapy is currently being challenged to dual therapy 4

ONGOING TRIALS IN PATIENTS WITH AF UNDERGOING A PCI WITH STENTING Studies PIONEER AF-PCI RE-DUAL PCI Interventions Safety of two rivaroxaban regimens vs VKA Efficacy and safety of dual therapy with dabigatran vs. triple therapy with VKA www.clinicaltrials.gov 5

PIONEER AF-PCI: OVERVIEW PCI STUDY Objective: safety of two rivaroxaban regimens vs VKA after PCI (with stent placement) in non-valvular AF Rivaroxaban 15 mg od # + clopidogrel* Population: Paroxysmal, persistent or permanent AF, undergoing PCI (with stent placement) N=2100 R Rivaroxaban 2.5 mg bid + DAPT** Rivaroxaban 15 mg od # + low-dose ASA 1:1:1 Intended DAPT duration of 1, 6 or 12 months VKA (INR 2.0 3.0) + DAPT* VKA + low-dose ASA End of treatment (12 months) * alternative use of prasugrel or ticagrelor allowed, but capped at 15% ** ASA (75 100 mg daily) + clopidogrel (75 mg daily) (alternative use of prasugrel or ticagrelor allowed, but capped at 15%); # CrCl 30 49 ml/min: 10 mg od; First dose 72 96 hours after sheath removal; First dose 12 72 hours after sheath removal www.clinicaltrials.gov 6

RE-DUAL PCI STUDY Objective: to evalate two new regimens with dabigatran: 150 or 110 mg BID plus single antiplatelet Dabigatran 150 mg BID + P2Y12 inhibitor Population: NVAF, undergoing PCI (with stent placement) n=2840 pts per arm R Dabigatran 110 mg BID + P2Y12 inhibitor Warfarin (INR 2.0 3.0) + P2Y12 inhibitor + ASA www.clinicaltrials.gov 7

WHAT ARE THE REMAINING ISSUES? In patients with: Atrial fibrillation venous thromboembolism In at-risk clinical settings: Bleeding Urgent surgery or invasive procedure 8 8

MANAGEMENT OF ACUTE VENOUS THROMBOEMBOLISM META-ANALYTIC POOLING L. A. Castellucci et al. JAMA. 2014;312:1122-35. 9

MANAGEMENT OF ACUTE VENOUS THROMBOEMBOLISM META-ANALYTIC POOLING L. A. Castellucci et al. JAMA. 2014;312:1122-35. 10

ISSUES IN PATIENTS WITH VENOUS THROMBOEMBOLISM Use of DOACs in daily practice: In vulnerable patients In long term secondary prevention In patients with cancer-associated VTE 11 11

ISSUES IN PATIENTS WITH VENOUS THROMBOEMBOLISM Patient characteristics in trials comparing DOACs with conventional therapy for acute VTE treatment Dabigatran Rivaroxaban DVT and PE Apixaban Edoxaban Mean age ± SD (y) Age 75 y, n (%) 54.9 ±16.0 57.0 ± 17.0 57.0 ±16.0 55.8 ±16.3 529 (10) 1283 (15) 768 (14) 1104 (13) 12

THE XALIA STUDY Multicentre, prospective, non-interventional, observational study Evaluation of the effectiveness and safety of rivaroxaban compared with standard therapy in patients with DVT in a heterogeneous, unselected patient population in a real-world setting Results expected in 2015 13

ISSUES IN PATIENTS WITH VENOUS THROMBOEMBOLISM Use of DOACs in daily practice: In vulnerable patients In long term secondary prevention In patients with cancer-associated VTE 14 14

POTENTIAL OPTIONS FOR SECONDARY PREVENTION OF VTE META-ANALYTIC POOLING L. A. Castellucci et al. BMJ 2013;347:f5133 15

EFFICACY AND SAFETY OF VARIOUS AGENTS FOR THE SECONDARY PREVENTION OF VTE L. A. Castellucci et al. BMJ 2013;347:f5133 16

EINSTEIN CHOICE- STUDY DESIGN Aim of the study: Demonstrate that both rivaroxaban 20 mg or 10 mg are superior in the long term secondary prevention of recurrent VTE to ASA 100 mg with comparable rates of major bleeding Patients with confirmed symptomatic DVT and/or PE who completed 6-12 months of anticoagulant treatment Day 1 N~ 2,850 R Rivaroxaban 20 mg od n~ 950 Rivaroxaban 10 mg od n~ 950 ASA 100mg od n~ 950 12-month treatment duration 1 month observation period Multicenter, randomized, double-blind, double-dummy, active-comparator, event-driven, superiority study www.clinicaltrials.gov 17

ISSUES IN PATIENTS WITH VENOUS THROMBOEMBOLISM Use of DOACs in daily practice: In vulnerable patients In long term secondary prevention In patients with cancer-associated VTE 18

CAN DOACS BE USED IN PATIENTS WITH CANCER- ASSOCIATED VTE? Patients with cancer are at high risk of VTE often present several bleeding risk factors No significant difference for efficacy of DOACS in cancer patients as compared with the total studied population in phase III trials Limited number of patients with VTE and active cancer included in trials. 19

CAN DOACS BE USED IN PATIENTS WITH CANCER- ASSOCIATED VTE? Trials EINSTEIN DVT EINSTEIN-PE AMPLIFY RE-COVER HOKUSAI-VTE Interventions Rivaroxaban Enoxaparin/VKA Rivaroxaban Enoxaparin/VKA Apixaban Enoxaparin/VKA HNF or LMWH/Dabigatran HNF or LMWH/VKA Enoxaparin/Edoxaban Enoxaparin/VKA Subgroup of patients with active cancer, n (%) 118 (6.8) 89 (5.2) 138 (5.7) 121 (5.0) 66 (2.5) 77 (2.8) 64 (5.0) 57 (4.5) 378 (9.2) 393 (9.5) 20

WHAT ARE THE REMAINING ISSUES? In patients with: Atrial fibrillation venous thromboembolism In at-risk clinical settings: Bleeding Urgent surgery or invasive procedure 21

MANAGEMENT OF BLEEDING AND EMERGENCY PROCEDURES Idarucizumab : Binding affinity to dabigatran higher than the binding of dabigatran to thrombin Phase III RE-VERSE AD ongoing Schiele et al. Blood. 2013;121:3554-62 22

R-ANTIDOTE (PRT064445) : UNIVERSAL ANTIDOTE FOR A BROAD RANGE OF FXA INHIBITORS? A truncated form of inactive FXa with high affinity for FXa inhibitors Restoration of haemostasis in a liver laceration model in rabbits treated with rivaroxaban G. Lu et al. Nat. Med. 2013;19:446-51. 23

CONCLUSIONS Systematic reviews and meta-analyses have shown that DOACS compared with VKAs: reduced the absolute risk of stroke and of major bleeding in patients with AF had a similar risk of recurrence, with a lower risk for bleeding in patients with VTE 24

CONCLUSIONS There is a need for trials on: new antithrombotic strategies in patients on OAC who require PCI strategies in patients with major bleeding or who require an invasive procedure There is a need for real world data on the effectiveness and risk of bleeding in patients with VTE 25

NEW 2014 EUROPEAN JOINT CONSENSUS DOCUMENT ON MANAGEMENT OF NVAF AND ACS/PCI Lip et al. Eur Heart J 2014 doi:10.1093/eurheartj/ehu298 26

ISSUES IN PATIENTS WITH VENOUS THROMBOEMBOLISM Use of DOACs in daily practice: In vulnerable patients: Frail elderly patients Morbid obesity, very low body weight pregnant women and nursing mothers Major thrombophilic defects 27