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Blood Adv. 2018 Mar 27;2(6):715-730. doi: 10.1182/bloodadvances.2017013573.

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

Author information

1
Department of Cardiology and Cardiovascular Medicine, University of Tübingen, Tübingen, Germany.
2
Department of Cardiology, University Hospital Lübeck, Lübeck, Germany.
3
Bayer AG, Wuppertal, Germany.
4
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
5
The Vascular Biology Center of Excellence.
6
Department of Internal Medicine.
7
Department of Microbiology, Immunology, and Biochemistry, and.
8
Department of Surgery, University of Tennessee Health Science Center, Memphis, TN.
9
Joint Program of Biomedical Engineering, University of Tennessee Health Science Center and University of Memphis, Memphis, TN.
10
CirQuest Labs, LLC, Memphis, TN.
11
Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
12
Division of Cardiology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL.
13
Institute of Pharmacology, Catholic University School of Medicine, Rome, Italy.
14
Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands; and.
15
Center for Thrombosis and Haemostasis, Gutenberg University Medical Center, Mainz, Germany.

Abstract

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.

PMID:
29588304
PMCID:
PMC5873232
DOI:
10.1182/bloodadvances.2017013573
[Indexed for MEDLINE]
Free PMC Article

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