Inhibitory mechanisms of very low–dose rivaroxaban in non–ST-elevation myocardial infarction

• Published in: Blood advances 2018-03, Vol.2 (6), p.715-730
• Main Authors: Borst, Oliver, Münzer, Patrick, Alnaggar, Nada, Geue, Sascha, Tegtmeyer, Roland, Rath, Dominik, Droppa, Michal, Seizer, Peter, Heitmeier, Stefan, Heemskerk, Johan W.M., Jennings, Lisa K., Storey, Robert F., Angiolillo, Dominick J., Rocca, Bianca, Spronk, Henri, Ten Cate, Hugo, Gawaz, Meinrad, Geisler, Tobias
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Biomarkers; Blood Coagulation - drug effects; Blood Platelets - drug effects; Blood Platelets - metabolism; Clinical Trials and Observations; Factor Xa Inhibitors - administration & dosage; Female; Flow Cytometry; Humans; Inflammation Mediators - metabolism; Male; Middle Aged; Non-ST Elevated Myocardial Infarction - blood; Non-ST Elevated Myocardial Infarction - complications; Non-ST Elevated Myocardial Infarction - drug therapy; Platelet Activation - drug effects; Platelet Aggregation - drug effects; Rivaroxaban - administration & dosage; Thrombin - metabolism; Thrombosis - etiology; Thrombosis - prevention & control
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2017013573

Very low–dose (VLD) factor Xa (FXa) inhibition, in combination with acetylsalicylic acid (ASA) and clopidogrel, is associated with improved outcomes in patients with acute coronary syndrome (ACS) with a tolerable bleeding risk profile. To date, there are no data documenting platelet inhibition and the anticoagulatory effects of VLD FXa inhibition on top of guideline-adherent dual-antiplatelet therapy (DAPT) in patients with ACS. Patients with non–ST-elevation myocardial infarction (NSTEMI) receiving oral DAPT (ASA + clopidogrel, n = 20; or ASA + ticagrelor, n = 20) were prospectively enrolled in a nonrandomized study. Coagulation- and platelet-dependent thrombin generation (TG), measured by means of the calibrated automated thrombogram, were significantly decreased after in vitro and in vivo addition of rivaroxaban. As shown by a total thrombus-formation analysis approach, rivaroxaban treatment led to a significantly decreased coagulation-dependent (AR-chip) thrombus formation in patients treated with ASA plus P2Y12 inhibitor (clopidogrel/ticagrelor), whereas the pure platelet-dependent (PL-chip) thrombus formation was not affected at all. Adjunctive rivaroxaban therapy was not associated with significant differences in platelet aggregation assessed by light-transmission aggregometry (LTA). Nevertheless, according to fluorescence-activated cell sorter analysis, VLD rivaroxaban treatment resulted in a significantly reduced expression of platelet HMGB-1, whereas P-selectin exposure was not affected. Furthermore, an enhanced effect of rivaroxaban on total thrombus formation and TG was observed in particular in clopidogrel nonresponder patients defined as adenosine 5′-diphosphate-induced LTA ≥40%. VLD rivaroxaban reduces thrombus formation and platelet-dependent TG in patients with ACS receiving DAPT, which can be of potential ischemic benefit. This trial was registered at www.clinicaltrials.gov as #NCT01417884. •VLD rivaroxaban significantly reduces platelet-dependent thrombin generation and thrombus formation on top of DAPT in patients with ACS.•Adjunctive treatment with VLD rivaroxaban additionally reduced TG and thrombus formation in both clopidogrel responders and nonresponders. [Display omitted]