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Evaluating oral rivaroxaban- an anticoagulant-in cats

Dixon-Jimenez AC, Brainard BM, et al. Pharmacokinetic and pharmacodynamic evaluation of oral rivaroxaban in healthy adult cats. J Vet Emerg Crit Care (San Antonio, Tex. : 2016), 26(5), 619–29. 

The development of blood clots is a major issue in feline patients. The majority of blood clots in cats occur as a result of heart disease, though they may less commonly occur as a result of kidney disease, cancers, or other conditions. The classic presentation of a blood clot in a cat is “aortic saddle thrombus” or “Feline Arterial Throboembolism” (FATE). In this disease, a blood clot dislodges from the heart and travels down the aorta to lodge in the blood vessels of the hind legs resulting in pain, paralysis, and loss of function that may be fatal. Blood clots may also travel to the brain (stroke), lungs (pulmonary embolism), or other parts of the body. The use of anti-coagulants (commonly called “blood thinners”) to prevent blood from clotting is a key part of the management of heart disease and other hypercoaguable states in cats and humans.

Recent data (FATCAT, Reference 3) suggests that the use of clopidogrel (plavix) in cats with cardiomyopathy and previous thrombotic events decreases the risk of future blood clots, and that this therapy is superior to aspirin. However, some studies suggest that Plavix may be of limited efficacy in some cats.

Rivaroxaban (RVX) is a direct inhibitor of activated factor X (Xa). Factor Xa is the key player in the common pathway of coagulation through conversion of prothrombin into thrombin. By inhibiting its action, rivaroxaban decreases the risk of blood clot development. Patients on rivaroxaban have elevations to both dilute prothrombin time (dPT) and activated partial thromboplastin time (aPTT). In humans, RVX is used for the treatment of hypercoagulability in atrial fibrillation, deep vein thrombosis, coronary artery disease, and several other indications (such as after orthopaedic surgery). In these situations it has been shown to be non-inferior to warfarin. RVX carries several advantages over other therapies (such as clopidogrel, heparin and warfarin) in that it is orally administered, may carry a lower risk of bleeding, and does not require intensive monitoring. It also has several drawbacks, as it is non reversible and significantly more expensive than other options.

The authors of this study attempted to evaluate the safety, tolerability and efficacy of RVX when given to cats at various doses and intervals over both the long and short term. It did not attempt to determine the clinical effect of drug administration in animals at risk of thromboembolism.

6 adult cats (3 male and 3 female) were enrolled in this study. Cats were determined to be healthy after blood and urine analysis, blood pressure measurement, and echocardiography. Commercially available RVX tablets were fractioned and administered orally at doses of 1.25mg, 2.5mg, and 5mg per cat. Cats were evaluated after a single oral dose (at each dose), 3 days dosing (at 1.25mg every 12h), 7 day dosing (and 2.5mg every 24h), and 28 day dosing (and 1.25mg every 24h).

Cats were monitored for adverse effects including spontaneous bleeding and off target effects. None were observed. There were also no significant changes to biochemistry, hematology, or urinalysis results.  Efficacy of the drug was determined by measurements of aPTT, dPT, and anti-factor Xa activity (aXa). Serum RVX concentration was also determined by a tandem HPCL/MS analysis.

After a single dose there were dose related increases in all coagulation values. Peak plasma levels occurred 3 hours after administration. Coagulation values returned to normal after 24 hours at the two higher doses, but only seemed to last 12 hours at 1.25mg. After 28 days of dosing kinetics and dynamics were very similar to initial therapy, however in some animals aXa was slightly lower, suggesting some degree of increased metabolism may be occurring.

This study found that oral administration of rivaroxaban to cats was safe and well tolerated over a range of doses. In both short and long term dosing there were no significant bleeding events or changes to serum biochemisty, CBC or urinalysis. All doses tested resulted in an inhibition of factor Xa within the target range for anti coagulation in humans. Drug kinetics also closely mirrored those seen in human trials. Dosing at 2.5-5 mg every 24 hours, or 1.25mg every 12 hours is likely an effective range for most cats.

There were several limitations to this study. Sample sizes were very small and results may differ in larger scale analysis. All cats enrolled in the study were healthy, and the drug may exhibit different kinetics and dynamics in sick animals, especially those with coagulopathy. Finally, this study only examined laboratory values after drug administration; it did not evaluate outcome-based measurements such as decreased risk of vascular events.

Despite these limitations, this paper provides evidence that rivaroxaban may be an effective anticoagulant in cats and sets the ground work for further outcome based trials evaluating the efficacy in clinical situations. (MRK)

See Also
Hogan DF, Fox PR, Jacob K, et al. Secondary prevention of cardiogenic arterial thromboembolism in the cat: the double-blind, randomized, positive-controlled feline arterial thromboembolism; clopidogrel vs. aspirin trial (FAT CAT). J Vet Cardiol 2015; 17(Suppl 1):S306–S317.