Anticoagulant Treatment for Deep Venous Thrombosis Direct Oral Anticoagulants (NOACs)

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1 Anticoagulant Treatment for Deep Venous Thrombosis Direct Oral Anticoagulants (NOACs) Prof. P. HAINAUT Médecine Interne - Maladie Thromboembolique Cliniques Univ. Saint Luc - UCL

2 Background Direct Oral Anticoagulants Pharmacological characteristics Efficacy and Safety (clinical trials) Common and specific findings Anticoagulant measurement Neutralisation Duration of anticoagulation Conclusion

3 Venous Thromboembolism VKA 3-6 months... INR 2 INR 2 24 h LMWH, UFH, Fondaparinux 5 days Acute Intermediate Unprovoked VTE Recurrence : 6-10%/y Increased risk for arterial thrombosis Prolonged

4 VKA treatment Interindividual and intraindividual variability due to genetic and environnemental factors Multiple drug and food interactions Costly and inconvenient monitoring Thrombosis Narrow therapeutic window Bleeding Narrow therapeutic target Efficiency and safety depending on the quality of INR control. Dose Ansell et al., Chest 2004; Hirsh et al., Chest 2004

5 Direct Oral Anticoagulants Dabigatran etexilate Pradaxa Rivoraxaban Xarelto Apixaban Eliquis Edoxaban Lixiana Target IIa Xa Xa Xa Prodrug Yes No No No Availability 6,5 % 80 % (food) 66 % 60 % Cmax 2-4h 2-4h 3-4h 1-3h Half-life 12-17h 7-11h 8-15h 9-11h Dosing 2x/d 1x/d 2x/d 1x/d Renal elimin 80 % 33 % 25 % 35 % CYP metabol No 32 % (3A4;2J2) Minimal (3A4) <4% Carrier P-gp P-gp/BCRP P-gp/BCRP P-gp Prot. binding 30 % 92 % 90 % 50 %

6 Venous Thromboembolism VKA 3-6 months... INR 2 INR 2 24 h LMWH, UFH, Fondaparinux 5 days Acute LMWH, UFH, Fondaparinux Intermediate Prolonged Dabigatran - Edoxaban Rivaroxaban - Apixaban

7 PRIMARY EFFICACY RE-COVER I/II n = 5128 EINSTEIN-DVT EINSTEIN-PE n = 8281 AMPLIFY n = 5244 HOKUSAI-VTE n= 8240 Dabig VKA Rivarox VKA Apix VKA Edox VKA Primary efficacy outcome n (%) 30 (2,4) 27 (2,1) 86 (2,1) 95 (2,3) 59 (2,3) 71 (2,7) 130 (3,2) 146 (3,5) HR 1,1 0,89 0,84 0,89 95% CI 0,65-1,84 0,66-1,19 0,6-1,18 0,7-1,13 prespecified non inferior margin 2,75 2,0 1,8 1,5 p-value < 0,0001 < 0,0001 < 0,0001 < 0,0001

8 BLEEDING RE-COVER I/II n = 5128 EINSTEIN-DVT EINSTEIN-PE n = 8281 AMPLIFY n = 5244 HOKUSAI-VTE n= 8240 Dabi VKA Riva VKA Apix VKA Edox VKA Major or NMCR bleeding n (%) 71 (5,6) 111 (8,8) 388 (9,4) 412 (10) 115 (4,3) 261 (9,7) 349 (8,5) 423 (10,3) HR 95% CI 0,63 0,47-0,84 0,93 0,81-1,06 0,44 0,36-0,55 0,81 0,71-0,94 Major bleeding n (%) 20 (1,6) 24 (1,9) 40 (1,0) 72 (1,7) 15 (0,6) 49 (1,8) 56 (1,4) 66 (1,6) HR 95% CI 0,82 0,45-1,48 0,54 0,37-0,79 0,31 0,17-0,55 0,84 0,59-1,21

9 DOACs : efficacy and safety Initial phase Intermed Prolonged phase Efficacy vs VKA Safety vs VKA Major bleeds Safety vs VKA CR non major bleeds Safety vs VKA All bleeds Reduced Dose Dabigatran Pradaxa LMWH 5-7 d 150 mg 2x = = - Rivaroxaban Xarelto 15 mg 2 x 3 weeks 20 mg 1 x = = = - Apixaban Eliquis 10 mg 2 x 1 week 5 mg 2 x = = - Edoxaban LMWH 5-7 d 60 mg 1 x = = 30 mg 1x ClCr < 50 ou < 60 kg

10 DOACs Efficacy Van der Hulle et al. J Thromb Haemost 2014; 12: 320-8

11 DOACs Safety Van der Hulle et al. J Thromb Haemost 2014; 12: 320-8

12 Common findings High number of patients Rather coherent results between trials DOACs : efficacy non inferior than VKA Increased safety regarding major bleedings and/or CRNM and major bleedings, bleeding at critical site including intracranial bleeding Specific findings DOACs in VTE Rivaroxaban : improved safety profile in fragile patients Edoxaban : increased efficacy in submassive PE Apixaban : very low rate of major bleedings

13 DOACs et interactions Gong IY & Kim RB, Can J Cardiol 2013;29:S24-S33

14 Drug-drug interactions Mechanisms Dabigatran etexilate Rivoraxaban Apixaban Edoxaban HIV protease inhibitors P-gp/3A4/ BCRP? +153%?? Rifampicin, millepertuis, carbamazepin phenytoin P-gp/ 3A4/2J2/ BCRP - 66% -50 % -54 % -35 % Don t use Careful dose reduction not clinically significant

15 Drug-drug interactions Mécanisme Dabigatran etexilate Rivoraxaban Apixaban Edoxaban Verapamil P-gp/3A %?? +53% Diltiazem P-gp/3A4 -? +40%? Quinidine P-gp +50% +50%? +80% Amiodarone P-gp % - Ketocon-,itra con-,voricon, posaconazol Prise P-gp/3A4/ BCRP 2x/j % +160% +100%? Fluconazole 3A4? +42%?? Cyclosporin Tacrolimus Clarithro-, érythromycine Don t use P-gp? +50%?? P-gp/3A % %?? Careful Dose reduction not clinically significant

16 Direct Oral Anticoagulants NO REGULAR MONITORING Measurement if : Measurement : when and why? RECURENCE - treatment failure? - lack of compliance? - interfering medications? BLEEDING - overdosage? - accumulation? EMERGENCY PROCEDURE - residual anticoagulation? SPECIFIC PROFILE - very low or high weight - renal or liver impairment

17 Direct Oral Anticoagulants Anticoagulation measurement : which tests? Time elapsed from last administration Relationship with safety/efficacy yet poorly defined Anti-IIa (dabigatran) : aptt : bleeding target 80 sec (through, bid) Hemoclot : thrombine time (diluted TT), linear correlation with plasma level of dabigatran Anti-Xa (rivaroxaban, apixaban,...) : INR : unsuitable; PT : prolonged (rivaroxaban) Chromogeninc test anti-xa (commercialisé) : specific; correlated with concentration sensitive for a large spectrum of concentration

18 DOACs neutralization Today PCC (PPSB) : 25 U/kg apcc (Feiba) : higher cost; thromboti risk? rfviia : not recommended Tomorrow...

19 DOACs Neutralization Agent Structure Mechanism Kinetics Clinical use PRT (Portola) Andexanet alfa f. Xa recombinant human activity high affinity - anti-xa - hépar-at t1/2 : 6h neutralisation > 90% IV 420 mgperfusion adabi-fab (Boehringer Ingelheim) Fab humanized non competitive high affinity Dabigatran activity t1/2 : 45 min neutralisation complete IV 2000 mg PER977 (Perosphere/Daiichi Sankyo) synthetic covalent binding - anti-xa - anti-iia - HBPM - fondaparinux ex-vivo

20 VTE : duration of anticoagulation (ACCP 2012) PE, DVT proximal or distal, related to surgery PE, DVT proximal or distal, related to transient risk factor ( surgery) PE, DVT proximal (distal), Idiopathic, 1st episode Cancer, relapse(s), severe thrombophilia, anti-phospholipids 3 months (1B) 3 months 3 months ---> prolonged prolonged

21 Conclusions (I) For VTE treatment, DOACs are appropriate for most patients : more convenient : no regular monitoring reduction of major, intracranial and fatal bleeding reduction of drug interactions lack of food interactions Monitor renal function ( 1x/year) Assess compliance Follow registries data : real life!

22 Conclusions (II) DOACs are not indicated for every patient Specific indications for LMWH, VKA Gastro-intestinal, urologic bleedings, epistaxis... Contra-indications : Severe renal failure 15 ml/min : absolute ml/min : not recommended, dabigatran contraindicated Drug interactions Pregnancy, breast-feeding