Chances and risks of direct oral anticoagulants for VTE

LINC, Leipzig, 26.01.2016 Chances and risks of direct oral anticoagulants for VTE E. Lindhoff-Last Cardioangiologisches Centrum Bethanien (CCB) CCB Gefäß Centrum CCB Gerinnungs Centrum CCB Studien Centrum Frankfurt Germany

Conflicts of interest Research Support: Bayer Vital, BMS/Pfizer, Daiichi Sankyo, Werfen, Roche Diagnostics Presentations: Bayer Vital, Boehringer Ingelheim, Pfizer/BMS, Daiichi Sankyo, CSL Behring, Werfen, Roche Diagnostics, Stago Advisory Boards: Bayer Vital, Boehringer Ingelheim, Pfizer/BMS, Daiichi Sankyo, Werfen, Roche Diagnostics, Stago

Comparison of direct oral anticoagulants (DOAC) Direct oral inhibition Dabigatran Pradaxa Factor IIa (Prodrug) Rivaroxaban Xarelto Apixaban Eliquis Edoxaban Lixiana Factor Xa Factor Xa Factor Xa Bioavailability 6,5 % 80 100 % 50 % 62 % Tmax 0,5 2 h 2 4 h 3 4 h 1 2 h T 1/2 12 17 h 5 9 h 11 13 h (older patients) 12 h 9 10 h Renal Elimination 85 % 33 % 27 % 35 39 % Antidote Yes No No No Acute therapy and secondary prevention of VTE Extended secondary prevention of VTE 1 week LMWH followed by 2x 150 mg bid (2x 110 mg bid)* 2x 150 mg bid (2x 110 mg bid)* 2x 15 mg bid (3 weeks) followed by 1x 20 mg od (1x 15 mg od)* 1x 20 mg od (1x 15 mg od)* *Dose reductions depending on renal function, age etc. 2x 10mg bid (1 week) followed by 2x 5 mg bid 2x2.5 mg bid Prophylactic dose 1 week LMWH followed by 1x60mg od (1x30mg od)* _ Modified according to Schulman, Thromb Haemost 2014 sowie den Fachinformationen der Hersteller Apixaban und Rivaroxaban Juli 2014; Dabigatran 06/2014; Edoxaban FDA Draft briefing document 2014

NDOAC: acute treatment and secondary prevention - efficacy Van der Hulle et al., J Thromb Haemost. 2014; 12:320-328 Van der Hulle et al. J Thromb Haemost 2014; 12: 320-328 5 studies; DOAC in comparison to Warfarin (non-inferiority-studies) n=24.455 patients with VTE 44% acute pulmonary embolism, TTR Warfarin: 58% - 64% No difference in recurrence of VTE (2.0 % DOAC vs. 2.2% Warfarin) and mortality

DOAC: acute treatment and secondary prevention of VTE: Bleeding Van der Hulle et al., J Thromb Haemost. 2014; 12:320-328 Van der Hulle et al. J Thromb Haemost 2014; 12: 320-328 major bleeding sign. reduction 40% intracranial bleeding sign. reduction 61% major GI-bleeding no sign. difference fatal bleeding sign. reduction 64% DOAC in comparison to Warfarin: significantly reduced major, intracranial and fatal bleeding

DOAC: VTE Treatment Chances DOAC in comparison to Enoxaparin + Warfarin equally effective in prevention of recurrent VTE Improved safety because of significant reduction of major and intracranial bleeding

Metaanalysis: DOAC: Prolonged secondary prevention Comparison vs placebo: efficacy + safety Placebo - 92% Placebo Placebo Placebo - 82% - 67% No major bleeding risk Prophylactic dose of apixaban (2x2.5mg) highly effective in prevention of recurrent VTE without increased bleeding risk Schulman, Thromb Haemost 2014; Apr 1;111(4):575-82

Conclusions: Prolonged secondary prevention with DOAC Prolonged secondary prevention with DOAK is effective in reducing recurrent VTE in high risk patient populations in comparison to placebo For the first time a prophylactic dose of apixaban (2x2.5mg) is effective without increased major bleeding risk (after 6 months of secondary prevention) Chance: safe long term anticoagulation in high risk patients now possible!

Perioperative Management Stop DOAC- no bridging with heparin! OP Heparin-bridging increases bleeding risk significantly Beyer-Westendorf et al European Heart J 2014 35: 1888-1896

Risk of Non-adherence short half life time of DOAC! Costs because of non-adherence in Germany: 7.5 10 billion Euro! 20 % of patients refer exactly to prescription 40 % take the medication most of the time Gräf M. Bayreuth, P.C.O.-Verlag 2007 20 % of patients take their medication irregularly 20 % of patients are non-compliant Deutscher Apothekerverband ABDA - Ref. 2002; Pharmazeutische Zeitung 47,2007; DiMatteo. Med Care 2004;42:200-209 Registry-data: Non-adherence VKA: 22 58 % Non-adherence DOAC: 2 37 % New interventions are urgently needed to improve patient adherence, ie monitoring, mobile communication including e-mails, SMS etc., no studies yet available de.123rf.com Rodriguez et al., J Thromb Haemost 2013; Gorst-Rasmussen et al, J Thromb Haemost 2015; Shore et al, Am Heart J 2014; Beyer-Westendorf et al, Europace 2015; Beyer-Westendorf et al, Thromb Haemost 2015

DOAC How to reduce risks? Before start of medication with DOAC check creatinine clearance and adopt dosage, During treatment check renal function regularly in case of Expected deterioration of renal function (ie. dehydratation, co-medication which might influence pharmacokinetics) 2 4x /year (?) in patients > 75 years and/or in patients with reduced renal function before elective invasive procedures especially in old, fragile patients

Thank you for your attention Cardioangiologisches Centrum Bethanien (CCB) CCB Vascular Center CCB Coagulation Center CCB Coagulation Research Center Frankfurt Germany www.ccb.de