Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT)

Hogan, Daniel F.; Fox, Philip R.; Jacob, Kristin A.; Keene, Bruce W.; Laste, Nancy J.; Rosenthal, Steven J.; Sederquist, K.D.; Weng, Hsin‐Yi

doi:10.1016/j.jvc.2015.10.004

Cited by 95 publications

(133 citation statements)

References 25 publications

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“…In people, the two distinct peaks represent the formation of both the H3 (inactive) and H4 (active) diastereoisomers. We suspect that the single peak in cats either represents the H2 or H4 diastereoisomer because the H2 and H4 isomers are the only active isomers of CAM (10) and because platelet inhibition by clopidogrel in cats has been demonstrated (1, 7). Based on the retention time of the CAM-D peak in cats, the peak is would be most consistent with H4.…”

Section: Discussionmentioning

confidence: 99%

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Validation of a method for quantitation of the clopidogrel active metabolite, clopidogrel, clopidogrel carboxylic acid, and 2-oxo-clopidogrel in feline plasma

Lyngby

Court

Lee

2017

Journal of Veterinary Cardiology

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Objectives To validate a new method for stabilization and quantitation of the clopidogrel active metabolite (CAM), clopidogrel, and inactive clopidogrel carboxylic acid and 2-oxo-clopiodgrel. Animals Feline plasma was used for assay validation. A pilot pharmacokinetic study was conducted with 2 healthy cats. Methods CAM stabilization was achieved by adding 2-bromo-3′methoxyacetophenone to blood tubes to form a derivatized CAM (CAM-D). CAM-D was quantified using high performance liquid chromatography and tandem mass spectrometry. Validation of the methodology included evaluation of calibration curve linearity, accuracy and precision, and stability using quality control samples spiked with CAM-D, clopidogrel, clopidogrel carboxylic acid, and 2-oxo-clopidogrel. In vivo utility of this assay was evaluated by conducting a pharmacokinetic study in cats receiving a single oral dose of 18.75mg clopidogrel. Results The 2-oxo-clopidogrel metabolite was unstable. CAM-D, clopidogrel, and clopidogrel carboxylic acid appear stable for 1 week at room temperature and 9 months at −80°C. Standard curves showed linearity for CAM- D, clopidogrel, and clopidogrel carboxylic acid (r>0.99). Between assay accuracy and precision was ≤2.6% and ≤2.8% for CAM-D and ≤17.9% and ≤11.3% for clopidogrel and clopidogrel carboxylic acid. Within assay precision for all three compounds was ≤7%. All three compounds were detected in plasma from healthy cats receiving clopidogrel. Conclusions This methodology is accurate and precise for simultaneous quantitation of CAM-D, clopidogrel, and clopidogrel carboxylic acid in feline plasma but unsuitable for 2-oxo-clopidogrel. Validation of this assay is the first step to more fully understanding the use of clopidogrel in cats in both a population and individual setting.

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Section: Discussionmentioning

confidence: 99%

“…Clopidogrel is an antiplatelet agent commonly used in cats and is superior to aspirin in the prevention of feline cardiogenic thromboembolism (1). Prevention of thromboembolic disease is paramount since survival rates post-embolism are low (less than 40%) with an approximate 17–75% recurrence rate (2, 3).…”

Section: Introductionmentioning

confidence: 99%

Validation of a method for quantitation of the clopidogrel active metabolite, clopidogrel, clopidogrel carboxylic acid, and 2-oxo-clopidogrel in feline plasma

Lyngby

Court

Lee

2017

Journal of Veterinary Cardiology

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“…Most cats with HCM receive long‐term antiplatelet medication and would clearly benefit from regular assessment of drug efficacy. However, a single study in cats suggests clopidogrel is more efficacious in preventing a thromboembolic event . In humans however, evidence exists that aspirin monotherapy is more efficacious in preventing thromboembolism in cardiovascular disease .…”

Section: Discussionmentioning

confidence: 99%

“…The optimum dose of clopidogrel in individual dogs remains unclear, and at least in humans, there is considerable variation in efficacy between individuals . In addition to unclear dosing strategies, assessing the efficacy of any antiplatelet medication is challenging, largely revolving around the absence of major thrombotic events . This approach has clear limitations as a surrogate marker.…”

mentioning

confidence: 99%

A Remote Assay for Measuring Canine Platelet Activation and the Inhibitory Effects of Antiplatelet Agents

Dunning

May

Adamany

et al. 2017

Veterinary Internal Medicne

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BackgroundAntiplatelet medications are increasingly used in dogs. Remote analysis of platelet activity is challenging, limiting assessment of antiplatelet drug efficacy.Hypothesis/ObjectivesTo evaluate a method used in humans for stimulation and remote analysis of canine platelet activity.AnimalsForty‐five dogs of various ages without a coagulopathy or thrombocytopenia. Six were receiving antiplatelet medication.MethodsProspective observational study. Platelets were stimulated with combinations of arachidonic acid (AA) and epinephrine (Epi) or adenosine diphosphate (ADP) and the thromboxane A2‐mimetic U46619 (U4). PAMFix was added to the blood samples to facilitate delayed analysis of platelet activity. Activity was assessed by flow cytometric measurement of surface P‐selectin (CD62P) expression.ResultsCanine platelets could be stimulated with both AA/Epi and ADP/U4. The levels of P‐selectin were significantly greater than paired, unstimulated samples (P < 0.001). Inhibition of P‐selectin expression occurred after this stimulation by adding antiplatelet drugs in vitro. The efficacy of antiplatelet drugs in samples from treated dogs was also measurable ex vivo using this method. Delayed analysis of platelet activity at time points up to 22 days demonstrated excellent correlation between respective mf values at each time point (r2 = 0.92, P < 0.0001).Conclusions and Clinical ImportanceThis study evaluated a new method to remotely assess canine platelet activity. It shows that PAMFix can be used for this purpose. This provides opportunities to interrogate the inhibitory action of antiplatelet drugs in clinical settings.

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“…The median survival time for cats treated with aspirin was 192 days, with only one cat having adverse drug events that required removal from the study. The survival time for cats treated with clopidogrel, however, was significantly longer than for cats treated with aspirin (Hogan et al ., ).…”

Section: Inhibitors Of Platelet Activationmentioning

confidence: 99%

Anti‐platelet therapy in small animal medicine

Thomason

Lunsford

Mackin

2016

Vet Pharm & Therapeutics

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Thromboembolism is a significant complication in many commonly encountered diseases, and can be a devastating sequel to otherwise treatable conditions. Platelets play an essential role in the hemostatic process and, consequently, are associated with thrombus formation. Platelets adhere to denuded vascular subendothelium, recruit additional platelets and cells, aggregate, and provide the catalytic surface for thrombin production and fibrin formation. Therapy to prevent unwanted thrombus formation and thromboembolic crises is essential in the management of hypercoagulable patients. Unfortunately, many of the medications used in veterinary medicine that inhibit or modulate coagulation factors, such as the heparins, are cost prohibitive, only effective when administered by injection or require frequent drug monitoring, and are therefore poor choices for long term at home therapy. While the role of the platelet in pathologic thrombus formation is not fully understood, veterinarians often resort to anti-platelet therapy in the management of patients at risk for thromboembolic complications, because many anti-platelet medications are inexpensive, require minimal drug monitoring, and can be given orally. The aim of this review is to discuss the anti-platelet therapies that are currently being used or being considered for use to inhibit platelet function and reduce thromboembolic complications in hypercoagulable dogs and cats.

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Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT)

Cited by 95 publications

References 25 publications

Validation of a method for quantitation of the clopidogrel active metabolite, clopidogrel, clopidogrel carboxylic acid, and 2-oxo-clopidogrel in feline plasma

Validation of a method for quantitation of the clopidogrel active metabolite, clopidogrel, clopidogrel carboxylic acid, and 2-oxo-clopidogrel in feline plasma

A Remote Assay for Measuring Canine Platelet Activation and the Inhibitory Effects of Antiplatelet Agents

Anti‐platelet therapy in small animal medicine

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