Thromb Haemost 2022; 122(08): 1341-1351
DOI: 10.1055/a-1730-8725
Cellular Haemostasis and Platelets

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

1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
2   Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy
,
Francesco Franchi
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Fabiana Rollini
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Latonya Been
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Patrick Abou Jaoude
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Andrea Rivas
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Xuan Zhou
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Sida Jia
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Naji Maaliki
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Chang Hoon Lee
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Andres M. Pineda
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Siva Suryadevara
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Daniel Soffer
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Martin M. Zenni
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
Tobias Geisler
3   Department of Cardiology and Angiology, University of Tübingen, Tübingen, Germany.
,
Lisa K. Jennings
4   MLM Medical Labs, LLC, Memphis, Tennessee, United States
,
Theodore A. Bass
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
,
1   Division of Cardiology, University of Florida College of Medicine, Jacksonville, Florida, United States
› Author Affiliations
Funding The present study was funded by an investigator-initiated grant from Janssen. Janssen had no role in study design conception, conduct of the study, or decision to publish these results.

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.

Clinical Trial Registration

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


Supplementary Material



Publication History

Received: 16 October 2021

Accepted: 22 December 2021

Accepted Manuscript online:
04 January 2022

Article published online:
14 February 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
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