Pharmacodynamic Profiles of Dual-Pathway Inhibition with or without Clopidogrel versus Dual Antiplatelet Therapy in Patients with Atherosclerotic Disease

Abstract

Aim Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy and how it compares to standard dual antiplatelet therapy (DAPT).

Methods and Results This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease—enrolled within a larger prospective, open-label, parallel-group PD study—who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI), or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF (collagen-related peptide + adenosine diphosphate [ADP] + tissue factor [TF]), markers of P2Y₁₂ reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and thrombin receptor-activating peptide [TRAP]), thrombin generation, and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend toward reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y₁₂ signaling and TRAP-induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase-1-mediated activity.

Conclusion Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations suggest that modulating thrombin generation—by means of factor Xa inhibition—in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of a DPI strategy observed in clinical trials.

Keywords

rivaroxaban - dual-pathway inhibition - dual antiplatelet therapy - atherosclerotic disease - clopidogrel - aspirin - pharmacodynamic

Clinical Trial Registration

http://www.clinicaltrials.gov. Unique Identifier: NCT03718429.

Publication History

Received: 16 October 2021

Accepted: 22 December 2021

Accepted Manuscript online:
04 January 2022

Article published online:
14 February 2022

• References

• 1 Rodriguez F, Harrington RA. Management of antithrombotic therapy after acute coronary syndromes. N Engl J Med 2021; 384 (05) 452-460
• 2 Angiolillo DJ, Galli M, Collet J-P, Kastrati A, O'Donoghue M. Antiplatelet therapy after percutaneous coronary intervention. EuroIntervention 2022; 17 (17) e1371-e1396
• 3 Knuuti J, Wijns W, Saraste A. et al; ESC Scientific Document Group. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J 2020; 41 (03) 407-477
• 4 Galli M, Capodanno D, Benenati S. et al. Efficacy and safety of dual pathway inhibition in patients with cardiovascular disease: a systematic review and Meta-analysis. Eur Heart J Cardiovasc Pharmacother 2021;
• 5 Eikelboom JW, Connolly SJ, Bosch J. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in stable cardiovascular disease. N Engl J Med 2017; 377 (14) 1319-1330
• 6 Anand SS, Bosch J, Eikelboom JW. et al; COMPASS Investigators. Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 219-229
• 7 Connolly SJ, Eikelboom JW, Bosch J. et al; COMPASS investigators. Rivaroxaban with or without aspirin in patients with stable coronary artery disease: an international, randomised, double-blind, placebo-controlled trial. Lancet 2018; 391 (10117): 205-218
• 8 Anand SS, Caron F, Eikelboom JW. et al. Major adverse limb events and mortality in patients with peripheral artery disease: the COMPASS trial. J Am Coll Cardiol 2018; 71 (20) 2306-2315
• 9 Bonaca MP, Bauersachs RM, Anand SS. et al. Rivaroxaban in peripheral artery disease after revascularization. N Engl J Med 2020; 382 (21) 1994-2004
• 10 Capodanno D, Mehran R, Valgimigli M. et al. Aspirin-free strategies in cardiovascular disease and cardioembolic stroke prevention. Nat Rev Cardiol 2018; 15 (08) 480-496
• 11 Galli M, Capodanno D, Andreotti F, Crea F, Angiolillo DJ. Safety and efficacy of P2Y₁₂ inhibitor monotherapy in patients undergoing percutaneous coronary interventions. Expert Opin Drug Saf 2021; 20 (01) 9-21
• 12 Franchi F, Rollini F, Faz G. et al. Pharmacodynamic effects of vorapaxar in prior myocardial infarction patients treated with potent oral P2Y₁₂ receptor inhibitors with and without aspirin: results of the VORA-PRATIC study. J Am Heart Assoc 2020; 9 (08) e015865
• 13 Franchi F, Rollini F, Kairouz V. et al. Pharmacodynamic effects of vorapaxar in patients with and without diabetes mellitus: results of the OPTIMUS-5 Study. JACC Basic Transl Sci 2019; 4 (07) 763-775
• 14 Franchi F, Rollini F, Garcia E. et al. Effects of edoxaban on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel: results of the EDOX-APT study. Thromb Haemost 2020; 120 (01) 83-93
• 15 Lancaster GA, Dodd S, Williamson PR. Design and analysis of pilot studies: recommendations for good practice. J Eval Clin Pract 2004; 10 (02) 307-312
• 16 Sibbing D, Aradi D, Alexopoulos D. et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y₁₂ receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv 2019; 12 (16) 1521-1537
• 17 Mehran R, Rao SV, Bhatt DL. et al. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation 2011; 123 (23) 2736-2747
• 18 Weitz JI. Insights into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014; 112 (05) 924-931
• 19 Galli M, Andreotti F, D'Amario D. et al. Antithrombotic therapy in the early phase of non-ST-elevation acute coronary syndromes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother 2020; 6 (01) 43-56
• 20 Biasucci LM, La Rosa G, Pedicino D, D'Aiello A, Galli M, Liuzzo G. Where does inflammation fit?. Curr Cardiol Rep 2017; 19 (09) 84
• 21 Loeffen R, van Oerle R, Leers MPG. et al. Factor XIa and thrombin generation are elevated in patients with acute coronary syndrome and predict recurrent cardiovascular events. PLoS One 2016; 11 (07) e0158355
• 22 Merlini PA, Bauer KA, Oltrona L. et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation 1994; 90 (01) 61-68
• 23 Weitz JI, Angiolillo DJ, Geisler T, Heitmeier S. Dual pathway inhibition for vascular protection in patients with atherosclerotic disease: rationale and review of the evidence. Thromb Haemost 2020; 120 (08) 1147-1158
• 24 Benenati S, Galli M, De Marzo V. et al. Very short vs. long dual antiplatelet therapy after second generation drug-eluting stents in 35 785 patients undergoing percutaneous coronary interventions: a meta-analysis of randomized controlled trials. Eur Heart J Cardiovasc Pharmacother 2021; 7 (02) 86-93
• 25 Benenati S, Crimi G, Canale C. et al. Duration of dual antiplatelet therapy and subsequent monotherapy type in patients undergoing drug eluting stent implantation: a network Meta-analysis. Eur Heart J Cardiovasc Pharmacother 2022; 8 (01) 56-64
• 26 Hiatt WR, Fowkes FGR, Heizer G. et al; EUCLID Trial Steering Committee and Investigators. Ticagrelor versus clopidogrel in symptomatic peripheral artery disease. N Engl J Med 2017; 376 (01) 32-40
• 27 Savarese G, Reiner MF, Uijl A. et al. Antithrombotic therapy and major adverse limb events in patients with chronic lower extremity arterial disease: systematic review and meta-analysis from the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy in Collaboration with the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases. Eur Heart J Cardiovasc Pharmacother 2020; 6 (02) 86-93
• 28 Bauersachs RM, Szarek M, Brodmann M. et al. Total ischemic event reduction with rivaroxaban after peripheral arterial revascularization in the VOYAGER PAD trial. J Am Coll Cardiol 2021; 78 (04) 317-326
• 29 Hiatt WR, Bonaca MP, Patel MR. et al. Rivaroxaban and aspirin in peripheral artery disease lower extremity revascularization: impact of concomitant clopidogrel on efficacy and safety. Circulation 2020; 142 (23) 2219-2230
• 30 Angiolillo DJ, Ueno M, Goto S. Basic principles of platelet biology and clinical implications. Circ J 2010; 74 (04) 597-607
• 31 Storey RF. Biology and pharmacology of the platelet P2Y12 receptor. Curr Pharm Des 2006; 12 (10) 1255-1259
• 32 Petzold T, Thienel M, Dannenberg L. et al. Rivaroxaban reduces arterial thrombosis by inhibition of FXa-driven platelet activation via protease activated receptor-1. Circ Res 2020; 126 (04) 486-500
• 33 Borst O, Münzer P, Alnaggar N. et al. Inhibitory mechanisms of very low-dose rivaroxaban in non-ST-elevation myocardial infarction. Blood Adv 2018; 2 (06) 715-730
• 34 Makhoul S, Panova-Noeva M, Regnault V, Ruf W, Wenzel P, Lagrange J. Rivaroxaban effects illustrate the underestimated importance of activated platelets in thrombin generation assessed by calibrated automated thrombography. J Clin Med 2019; 8 (11) 8
• 35 Perzborn E, Heitmeier S, Laux V. Effects of rivaroxaban on platelet activation and platelet-coagulation pathway interaction: in vitro and in vivo studies. J Cardiovasc Pharmacol Ther 2015; 20 (06) 554-562
• 36 Perzborn E, Heitmeier S, Buetehorn U, Laux V. Direct thrombin inhibitors, but not the direct factor Xa inhibitor rivaroxaban, increase tissue factor-induced hypercoagulability in vitro and in vivo. J Thromb Haemost 2014; 12 (07) 1054-1065
• 37 Siller-Matula JM, Lang I, Christ G, Jilma B. Calcium-channel blockers reduce the antiplatelet effect of clopidogrel. J Am Coll Cardiol 2008; 52 (19) 1557-1563