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1. Synergistic inhibitory effects of clopidogrel and rivaroxaban on platelet function and platelet‐dependent thrombin generation in cats

Author

Sara T. Lo, Ronald H. L. Li, Catherine J. Georges, Nghi Nguyen, Cheyenne K. Chen, Claire Stuhlmann, Maureen Sigmund Oldach, Victor Noel Rivas, Samantha Fousse, Samantha P. Harris, and Joshua A. Stern

Subjects
cardiology, cardiovascular, clopidogrel resistance, factor Xa inhibitor, hypertrophic cardiomyopathy, saddle thrombus, Veterinary medicine, SF600-1100
Abstract

Abstract Background Dual antithrombotic treatment (DAT) with clopidogrel and rivaroxaban sometimes is prescribed to cats with hypertrophic cardiomyopathy at risk of thromboembolism. To date, no studies have evaluated their combined effects on platelet function. Objectives/Hypothesis Evaluate the safety of DAT in healthy cats and compare, ex vivo, platelet‐dependent thrombin generation and agonist‐induced platelet activation and aggregation in cats treated with clopidogrel, rivaroxaban, or DAT. We hypothesized that DAT would safely modulate agonist‐induced platelet activation and aggregation more effectively than single agent treatment. Animals Nine apparently healthy 1‐year‐old cats selected from a research colony. Methods Unblinded, nonrandomized ex vivo cross‐over study. All cats received 7 days of rivaroxaban (0.6 ± 0.1 mg/kg PO), clopidogrel (4.7 ± 0.8 mg/kg PO), or DAT with defined washout periods between treatments. Before and after each treatment, adenosine diphosphate (ADP)‐ and thrombin‐induced platelet P‐selectin expression was evaluated using flow cytometry to assess platelet activation. Platelet‐dependent thrombin generation was measured by fluorescence assay. Platelet aggregation was assessed using whole blood impedance platelet aggregometry. Results No cats exhibited adverse effects. Of the 3 treatments, only DAT significantly decreased the number of activated platelets (P = .002), modulated platelet activation in response to thrombin (P = .01), dampened thrombin generation potential (P = .01), and delayed maximum reaction velocity (P = .004) in thrombin generation. Like clopidogrel, DAT inhibited ADP‐mediated platelet aggregation. However, rivaroxaban alone resulted in increased aggregation and activation in response to ADP. Conclusion and Clinical Importance Treatment combining clopidogrel and rivaroxaban (DAT) safely decreases platelet activation, platelet response to agonists, and thrombin generation in feline platelets more effectively than monotherapy with either clopidogrel or rivaroxaban.

Published
2023
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2. Dual therapy with clopidogrel and rivaroxaban in cats with thromboembolic disease

Author

Sara T. Lo, Ashley L. Walker, Ronald H L Li, Catherine J. Georges, and Joshua A. Stern

Subjects
medicine.medical_specialty, Cardiomyopathy, 040301 veterinary sciences, hypertrophic, 030204 cardiovascular system & hematology, Saddle thrombus, Cat Diseases, Article, 0403 veterinary science, 03 medical and health sciences, 0302 clinical medicine, Rivaroxaban, Internal medicine, clot, medicine, Animals, Humans, Thromboembolic disease, Veterinary Sciences, coagulation, Dual therapy, Small Animals, Retrospective Studies, platelet, CATS, factor Xa inhibitor, business.industry, Hypertrophic cardiomyopathy, Anticoagulants, Evaluation of treatments and therapeutic interventions, Venous Thromboembolism, 04 agricultural and veterinary sciences, medicine.disease, Clopidogrel, 6.1 Pharmaceuticals, Cats, Cardiology, Patient Safety, saddle thrombus, business, medicine.drug
Abstract

Objectives Feline arterial thromboembolism (ATE), an often devastating outcome, was recently shown to affect 11.3% of cats with hypertrophic cardiomyopathy over 10 years. Current American College of Veterinary Internal Medicine guidelines recommend the use of clopidogrel in cats at risk for ATE, with addition of a factor Xa inhibitor in very high risk or post-ATE cases. To date, no studies have examined the safety or efficacy of this combined antithrombotic therapy. This retrospective case series aimed to assess the frequency and type of adverse events that occurred in cats prescribed dual clopidogrel and rivaroxaban therapy. Secondary aims were to evaluate indications for dual therapy and clinical outcome. Methods The study included 32 cats prescribed clopidogrel (18.75 mg PO q24h) and rivaroxaban (2.5 mg PO q24h) on an outpatient basis over a 5-year period. Results Cats were prescribed dual therapy for at least one of the following: ATE event (n = 18), presence of an intracardiac thrombi (n = 17) or presence of spontaneous echocardiographic contrast (SEC) (n = 16). Five cats experienced adverse effects that could be attributed to medications, a median of 13 days from initiation (epistaxis, hematemesis, hematochezia or hematuria). No cat required hospitalization as a result of these events. Median survival time from onset of therapy was 257 days (interquartile range [IQR] = 38–497) for all cats, 502 days (IQR = 171–663) for ATE cats, 725 days (IQR = 133–856) for cats with an ATE to two or more limbs and 301 days (IQR = 221–431) for cats with only one limb affected. Recurrence rate of ATE while on dual therapy was 16.7%; no cat newly developed an ATE while on dual therapy. Conclusions and relevance Dual antithrombotic therapy with clopidogrel and rivaroxaban resulted in a low reported incidence of adverse events. Cats placed on dual therapy for an ATE event experienced a low rate of recurrence and effective thromboprophylaxis was achieved in cats with intracardiac thrombi or SEC.

Published
2021

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