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Novel Oral Anticoagulants (NOACs) in Veterinary Medicine

By Rebecca Quinn, DVM, DACVIM (Cardiology)
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 Thrombotic disease has been a well-recognized complication of human health for centuries.  Millennia, in fact, if one considers that Hippocrates was the first to identify a stroke in a human patient in the year 400 BC (1). Other than ischemic strokes, human thrombotic disease includes such conditions as myocardial infarction, deep vein thrombosis, and Budd-Chiari syndrome.  It is therefore interesting to take note of the timeline of anticoagulant therapies, which didn’t blossom until the use of heparin in the 1930s (2).  Over nearly 80 years, the medical community moved on to discover oral vitamin K antagonists (1940s), low-molecular weight heparin (1980s), and finally the first novel oral anticoagulant (NOAC) in 2008.  Reviewing this timeline, it is easy to understand why warfarin became almost a daily, household name: for over sixty years, warfarin was the only oral anticoagulant available to not only human, but veterinary patients.

In veterinary medicine, thrombosis is most often secondary to cardiac disease in cats (acquired cardiomyopathies), and associated with non-cardiac illness in dogs (most commonly immune-mediated hemolytic anemia, sepsis, neoplasia, Cushing’s disease and glomerular disease).3 Historically, the veterinary community relied on warfarin for at-home treatment of many thromboembolic diseases, and encountered challenges in terms of administration, monitoring, safety, and side effects.4,5  While other oral therapies have become available, mainly in the form of antiplatelet medications such as aspirin and clopidogrel (Plavix), another true oral anticoagulant has not been available until the introduction of the NOACs.

The NOACs, which are also referred to as “non-vitamin K oral anticoagulants,” inhibit the traditionally named extrinsic coagulation pathway.6  Specifically, they work by either inhibiting factor Xa (rivaroxaban and apixaban) or by directly inhibiting thrombin formation (dabigatran) (See Figure 16,7).  By interfering with the coagulation pathway at these levels, NOACs prevent the formation of fibrin and cross-linked fibrin clots.6 Ultimately, they help prevent thrombus formation with fewer side effects compared to warfarin.8  As a result, over the last ten years, NOACs have largely replaced warfarin in human medicine.  In observing our human counterparts and their overwhelmingly positive experiences with NOACs, we in the veterinary community are now exploring clinical opportunities in our patients.

Rivaroxaban (Xarelto) is the most well-studied NOAC in veterinary medicine.  It inhibits factor Xa, which therefore prevents the conversion of prothrombin to thrombin.6 Rivaroxaban has been established to effectively suppress thrombin formation in canine and feline patients, and has been demonstrated as a safe therapy (canine median dose 0.89 mg/kg by mouth once daily, feline dose range 1.25 – 5.0 mg per cat by mouth once to twice daily).9, 10,11 In a more clinical setting, rivaroxaban has been used to treat dogs with pulmonary embolism (PTE), arterial thromboembolism, and jugular vein embolism.12 In this particular case study, rivaroxaban was given at a dose range of 0.6 – 1.0 mg/kg by mouth once a day, with no obvious side effects, and apparent resolution of the thrombi.12

Figure 1. The figure below was borrowed from the journal Arteriosclerosis, Thrombosis, and Vascular Biology (reference 6), and demonstrates the site of action of the NOACs rivaroxaban, apixaban, and dabigatran.

A feline study is currently underway investigating the effectiveness of rivaroxaban as compared to clopidogrel in cats with cardiogenic thromboembolism. This study, called SUPER-CAT (study of the utility of rivaroxaban or clopidogrel for prevention and recurrent arterial thromboembolism in cats), is ongoing and organized by the University of Georgia with support from the Morris Animal Foundation.  Anecdotally, rivaroxaban at doses of 2.5 – 5.0 mg per cat by mouth once to twice daily has been used effectively and safely in cats with or at risk of cardiogenic thromboembolism.  Interestingly, clinicians have found that rivaroxaban can be combined with aspirin and/or clopidogrel therapy in feline patients who are very high risk for thromboembolic events. This offers potential multi-modal anticoagulation, and the risk of bleeding appears to be low.  Monitoring rivaroxaban in the laboratory setting is a challenge in veterinary medicine, as the species specific anti-factor Xa assay available to human patients is not available to cats or dogs.13 Prothrombin time can be measured to monitor for adverse effects, but this test is often only pursued if the veterinarian is concerned about excessive anticoagulation, or if the recommended doses are exceeded.  It is important to understand that the reversal agents available in human medicine have not been studied in veterinary patients, and are likely to be cost prohibitive; should a patient treated with rivaroxaban develop significant bleeding, this may be very difficult to control.14

Like rivaroxaban, apixaban (Eliquis) is a factor Xa inhibitor.  The differences between the two drugs can be found when reviewing the human-based pharmacokinetic properties.  Of note, apixaban has lower oral bioavailability, and less renal excretion as compared to rivaroxaban.15 Very little is known about apixaban use in dogs; there have been several pharmacokinetic studies in cats, indicating that apixaban at a dose of 0.625 mg per cat by mouth twice a day or 0.2 mg/kg by mouth once a day effectively inhibits factor Xa.16, 17 Preliminary data suggest that cats may develop nausea or vomiting with apixaban therapy, and patients should be monitored for gastrointestinal side effects.16  To date, there are no published or ongoing clinical studies assessing apixaban use in dogs or cats.

Dabigatran varies from the other members of the NOAC family in that it directly inhibits thrombin, which therefore prevents the conversion of fibrinogen to fibrin.6 It has the lowest oral bioavailability, is predominately renally excreted, and must be metabolized from its prodrug to active form.15  While studies indicate that that dabigatran is an effective anticoagulant in dogs, there is no clinical data supporting its use in either dogs or cats in the hospital setting.18

Novel oral anticoagulant therapy use in veterinary medicine is on the rise, and will likely continue to trend in that direction.  At the present time, rivaroxaban use is most supported, but therapy should be approached thoughtfully. As we continue to learn, one cannot help but hope that we will discover more effective means of treating our canine and feline patients with devastating thromboembolic disease. 

 

References

  1. Robicsek F et al. From Hippocrates to Palmaz-Schatz, the history of carotid surgery. European Journal of Vascular and Endovascular Surgery.  2004;27(4):389-397.
  2. Gray E et al. Heparin and low-molecular weight heparin. Thromb Haemost 2008;99(5):8-7-818
  3. Back J. Thromboembolic disease. DVM360 (online reference). 2011.
  4. Miller E. Immune mediated hemolytic anemia. Kirk’s Current Veterinary Therapy XIV. St. Louis, MO: Saunders Elsevier, 2009;266-271.
  5. Smith SA. Antithrombotic therapy. Top Companion Anim Med. 2012;27(2):88-94.
  6. Soff GA. A new generation of anticoagulants. Arterioscler Thromb Vasc Biol. 2012;32:569-574.
  7. Bashir S et al. A practical approach to the new oral anticoagulants used for stroke prevention in patients with atrial fibrillation. Journal of the Royal Coll Physicians 2016;46:113-118.
  8. Connolly SJ et al. Dabigatran versus warfarin in patients with atrial fibrillation. NEJM. 2009;261(12):1139-1151.
  9. Conversy et al. Rivaroxaban demonstrates in vitro anticoagulant effects in canine plasma. Vet J. 2013;198(2)437-443.
  10. Dixon-Jimenez AC et al. Pharmacokinetic and pharmacodynamics evaluation of oral rivaroxaban in healthy adult cats. JVECC. 2016;26(5):619-629.
  11. Morassi A et al. Evaluation of the safety and tolerability of rivaroxaban in dogs with presumed primary immune mediated hemolytic anemia. JVECC. 2016;26(4):488-494.
  12. Yang VK et al. The use of rivaroxaban for the treatment of thrombotic complications in four dogs. JVECC. 2016;26(5)729-736.
  13. Samamma MM et al. Laboratory assessment of rivaroxaban: a review. Thrombosis Journal. 2013:11(11):2-7.
  14. Christos S and Naples R. Anticoagulation reversal and treatment strategies in major bleeding: update 2016. West J Emerg Med. 2016;17(3):264-170.
  15. Massicotte A. A practice tool for the new oral anticoagulants. Candian Pharm Journal. 2014;147(1):25-32.
  16. Weder C et al. Multi-dose pharmacokinetics and pharmacodynamics of the commercially available formulation of oral apixaban in cats: a pilot study. ACVIM Proceedings 2015.
  17. Myers JA et al. Pharmakokinetics and pharmacodynamics of the Factor Xa inhibitor apixaban in cats: a pilot study. ACVIM Proceedings 2015.
  18. Rupin A et al. S35972, a direct-activing thrombin inhibitor with high oral bioavailability and antithrombotic efficacy. J Thromb Haemost. 2011;9(7):1375-1382.