Effect of rivaroxaban on thrombin generation is modified by a P2Y 12 receptor blocker

Transcription

1 Effect of rivaroxaban on thrombin generation is modified by a P2Y 12 receptor blocker E Perzborn, M Harwardt, S Heitmeier, V Laux Pharma R&D Discovery Research, Bayer Schering Pharma AG, Wuppertal, Germany This study was supported by Bayer Schering Pharma AG and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

2 Disclosures for Elisabeth Perzborn Employment Consultant Shareholder Speakers bureau Honoraria Scientific advisory board Bayer Schering Pharma No Bayer Schering Pharma No No No

3 Background is an oral, direct Factor Xa inhibitor that potently inhibits thrombin generation in human plasma is in advanced clinical development for the prevention and treatment of thromboembolic disorders ATLAS ACS TIMI 51 is the ongoing phase III study of rivaroxaban for secondary prevention after ACS versus standard of care (ASA and/or a thienopyridine) X-ray crystallographic image of the active-site pocket of Factor Xa Perzborn et al, 25; Gerotziafas et al, 27; Eriksson et al, 28; Lassen et al, 28; Turpie et al, 29; ATLAS ACS TIMI 51. Trial ID: NCT89965; Accessed 16 July 21; Roehrig et al, 25

4 Background Activation of coagulation and platelets are closely coupled Activated platelets provide a catalytic surface for initiating and sustaining coagulation; inhibiting platelet activation may affect thrombin generation (TG) In animal models of arterial thrombosis, adding rivaroxaban to clopidogrel or clopidogrel and ASA has been shown to significantly enhance antithrombotic effects Clopidogrel, a P2Y 12 receptor blocker, has been shown to significantly inhibit ex vivo TG in platelet-rich plasma of rats Ticagrelor is a reversible, direct-acting P2Y 12 receptor antagonist Our in vitro study used ticagrelor because it does not require metabolic activation, unlike the thienopyridines Mann et al, 199; Perzborn et al, 29; Hérault et al, 1999

5 Objectives To evaluate the effects of rivaroxaban with and without ticagrelor on thrombin generation in human platelet-rich plasma To assess the effect of the triple combination of rivaroxaban, ticagrelor and ASA

6 Thrombin (nm) Methods (I) Thrombin generation (TG) was triggered by tissue factor Thrombin activity was measured with a fluorogenic thrombin-specific substrate using the Calibrated Automated Thrombogram method 12 Peak TG (C max ) 8 Mean velocity = C max /T max lag time 4 Lag time Total thrombin (ETP) Time to peak (T max ) Time (minutes) Hemker et al, 23

7 Methods (II) Platelet-rich plasma from 11 healthy volunteers was spiked with the appropriate vehicle and/or : 15, 3, 6 ng/ml Ticagrelor:.1,.3, 1. µg/ml ASA: 1 µg/ml + ticagrelor + ticagrelor + ASA Plasma levels measured in patients : mean C max 39.8 ng/ml at 2.5 mg bid Ticagrelor: mean C max 81 ng/ml at 1 mg bid Mueck et al, 28; Husted et al, 26

8 Thrombin (nm) Thrombin (nm) or ticagrelor inhibited thrombin generation, but ASA did not concentrationdependently affected all parameters of TG Control 15 ng/ml 3 ng/ml 6 ng/ml ASA 1 µg/ml Peak TG (C max ) 6 Total thrombin (ETP) Lag time 3 Time to peak (T max ) Mean velocity ASA had no influence on any parameter Time (minutes) Control Ticagrelor.1 µg/ml Ticagrelor at 1. µg/ml affected Peak TG (C max ) Time to peak (T max ) 9 6 Ticagrelor.3 µg/ml Ticagrelor 1. µg/ml Mean velocity Time (minutes)

9 Thrombin (nm) Efficacy of rivaroxaban was enhanced with ticagrelor and/or ASA + ticagrelor Reduction of C max and mean velocity Prolongation of T max + ticagrelor + ASA Modest and consistent effect on these parameters Control Ticagrelor 1 µg/ml 6 ng/ml 6 ng/ml + ticagrelor 1 µg/ml 6 ng/ml + ticagrelor 1 µg/ml + ASA 1 µg/ml Time (minutes)

10 C max (nm thrombin) C max (nm thrombin) Effect on C max Control Ticagrelor ASA alone + Ticagrelor + Ticagrelor + ASA Ticagrelor.3 µg/ml Ticagrelor 1. µg/ml * ** ** ** ** ng/ml 3 ng/ml 6 ng/ml 15 ng/ml 3 ng/ml 6 ng/ml Combining rivaroxaban and ticagrelor has an additive effect and decreases peak thrombin generation more than each drug alone Combining rivaroxaban and ticagrelor with ASA consistently potentiates the inhibition of C max Data: mean ± SEM; *p<.5 vs control; **p<.1 vs control; p<.1 vs control

11 Mean velocity (nm thrombin/min) Mean velocity (nm thrombin/min) Effect on mean velocity Control Ticagrelor ASA alone + Ticagrelor + Ticagrelor + ASA Ticagrelor.3 µg/ml Ticagrelor 1. µg/ml * * 15 ng/ml 3 ng/ml 6 ng/ml 15 ng/ml 3 ng/ml 6 ng/ml Combining rivaroxaban and ticagrelor has an additive effect on mean velocity of TG Combining rivaroxaban and ticagrelor with ASA consistently potentiates the effect on mean velocity Data: mean ± SEM: *p<.5 vs control; **p<.1 vs control; p<.1 vs control

12 T max (min) T max (min) Effect on T max Control Ticagrelor ASA alone + Ticagrelor + Ticagrelor + ASA Ticagrelor.3 µg/ml Ticagrelor 1. µg/ml ** ng/ml 3 ng/ml 6 ng/ml 15 ng/ml 3 ng/ml 6 ng/ml Combining rivaroxaban and ticagrelor has an additive effect and increases time to peak of TG (T max ) Combining rivaroxaban and ticagrelor with ASA consistently potentiates time to T max Data: mean ± SEM; **p<.1 vs control; p<.1 vs control

13 Conclusions These results confirm that P2Y 12 receptor blockers inhibit thrombin generation Coagulation is a membrane-bound process including platelet membranes Reduced platelet activation affects thrombin generation, which may lead to the delayed formation of coagulation complexes plus clopidogrel and ASA has shown synergistic effects in animal thrombosis models The combination of rivaroxaban with single or dual antiplatelet drugs may result in increased antithrombotic efficacy Perzborn et al, 29; Becker et al, 21

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