Evidence collection14 June 2019

Antithrombotics in small animal veterinary practice

Evidence-based veterinary medicineSmall animalsMedicine

Introduction

Antithrombotics are medications that reduce the formation of blood clots. There are two classes of antithrombotics: anticoagulants and antiplatelet agents. In human medicine both anticoagulants (such as warfarin) and antiplatelet agents (such as low dose aspirin and clopidogrel) are widely used to reduce the risk of stroke, myocardial infarction, deep venous thrombosis (DVT) and pulmonary embolism. In human medicine there are evidence-based guidelines to support the use of these medications based on large scale randomized controlled studies.

The diseases associated with thrombosis in dogs and cats are different, not only from those seen in human medicine, but also from each other. None the less both species can be at risk for developing coagulation abnormalities leading to both venous and arterial thrombosis.

A recent special issue of the Journal of Veterinary Emergency and Critical Care includes a series of articles which make up the American College of Veterinary Emergency and Critical Care (ACVECC), Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines.

The guidelines were developed by a panel of experts who systematically reviewed the literature under five headings:

1. Defining populations at risk

2. Defining rational therapeutic usage

3. Defining antithrombotic protocols

4. Refining and monitoring antithrombotic therapies

5. Discontinuation of anticoagulant therapy in small animals

The working groups reviewed published studies, covering the 5 domains, using standardised worksheets, and generated 59 statements and 83 recommendations. These were refined through three rounds of Delphi surveys and presented and discussed at both the European Veterinary Emergency and Critical Care (EVECC) Congress and the International Veterinary Emergency and Critical Care Symposium (IVECCS) in 2018.

CURATIVE guidelines

Goggs, R. et al. (2019) American College of Veterinary Emergency and Critical Care (ACVECC) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines: Small animal. Journal of Veterinary Emergency and Critical Care 29 (1), pp. 12-36. https://doi.org/10.1111/vec.12801 [This article can be accessed via RCVS Knowledge Library Membership, click here]

This paper provides details of the methodology and a summary of the statements and recommendations divided under each of the 5 domains as well as the levels of evidence and degree of agreement for each of the statements / recommendations noting areas where evidence is lacking. Where there was insufficient evidence to provide specific recommendations there are suggestions based on the expertise of the contributors. The guidelines also include the full list of references for the papers that were reviewed

The guidelines are supported by five papers, each summarising the recommendations and literature relating to one of the domains. It should be noted that the guidelines and case scenarios concentrate on reducing the risk of thrombosis and use of antithrombotics and do not include mention of thrombolytic therapies.

Although the guidelines state that they are intended for use in “Academic and referral veterinary medical centers”, they are also supported by a paper uses clinical scenarios that demonstrate how the CURATIVE guidelines could be applied in practice.

Domain 1 – Defining populations at risk

The goal of Domain 1 was to establish disorders in which there is an association between disease and thrombosis and sought to determine to which patients antithrombotic medications should be administered. This paper presents a review of the evidence for diseases and risk factors using a standardized Population Exposure Comparison Outcome (PECO) question format was used to investigate whether in dogs or cats (Population, P), the development of a disease (Exposure, E), as opposed to remaining disease free (Comparison, C), was associated with the development of thrombosis (Outcome, O). Risk for thrombosis was further classified as “high,” “moderate,” or “low.”

Of the diseases evaluated, a high risk for thrombosis was identified in dogs with immune mediated haemolytic anaemia or protein-losing nephropathy and in cats with cardiomyopathy. However, it was also noted that it may be appropriate to use antithrombotics in those animals with more than one risk factor for thrombosis.

deLaforcade , A. et al (2022) 2022 Update of the Consensus on the rational use of antithrombotics and thrombolytics in veterinary critical care (CURATIVE) Domain 1—Defining populations at risk. Journal of Veterinary Emergency and Critical Care, 32 (3), pp. 289-314. https://doi.org/10.1111/vec.13204
deLaforcade, A. et al. (2019) Consensus on the rational use of antithrombotics in veterinary critical care (CURATIVE): Domain 1—Defining populations at risk. Journal of Veterinary Emergency and Critical Care, 29 (1), pp. 37-48. https://doi.org/10.1111/vec.12797
[This article can be accessed via RCVS Knowledge Library membership, click here]

Domain 2 – Defining rational therapeutic usage

Domain 2 sought to establish what drug or drug combination should be administered in venous and arterial thromboembolic disease settings in order to define rational therapeutic usage. The questions asked (i) when an antiplatelet agent versus an anticoagulant agent should be used; (ii) which antiplatelet agent is most effective in small animals; (iii) which anticoagulant agent is most effective in small animals; and (iv) when multimodal therapy is indicated.

They concluded that in diseases associated with venous thromboembolism (VTE) such as protein-losing nephropathy and immune-mediated haemolytic anaemia (IMHA) in dogs, thrombi are typically fibrin rich and their formation is less dependent upon platelet number or function. In contrast, in diseases associated with arterial thromboembolism (ATE) (such as feline cardiomyopathies), thrombi are typically platelet rich and hence antiplatelet agents may be most effective. However, they concede that these recommendations are based on pathophysiologic rationale and that as many hypercoagulable states in small animals can result in venous or arterial thrombosis in an unpredictable fashion, the judicious use of anticoagulants and antiplatelet drugs concurrently may also have merit.

The strong recommendations from this domain are

that antiplatelet agents be used for the prevention of ATE in cats
that clopidogrel be used instead of aspirin in cats at risk for ATE

Goggs, R. et al. (2019) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 2—Defining rational therapeutic usage. Journal of Veterinary Emergency and Critical Care, 29 (1), pp. 49-59. https://doi.org/10.1111/vec.12791 [This article can be accessed via RCVS Knowledge Library membership, click here]

Domain 3 – Defining antithrombotic protocols

The objective of Domain 3 was to determine whether some antithrombotic protocols are more effective than others in order to make recommendations about drug dose, the route and frequency of administration and also to highlight potential adverse effects.

Evidence-based recommendations concerning specific protocols could not be formulated for most antithrombotic drugs evaluated, either because of the wide range of dosage reported (e.g. aspirin in dogs) or the lack of evidence in the current literature. However, clopidogrel administration in dogs and cats at risk of arterial thrombosis, notably in cats at risk of cardiogenic thromboembolism, is supported by the literature, and specific protocols are recommended.

Blais, M-C. et al. (2019) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 3—Defining antithrombotic protocols. Journal of Veterinary Emergency and Critical Care, 29 (1), pp. 60-74. https://doi.org/10.1111/vec.12795 [This article can be accessed via RCVS Knowledge Library membership, click here]

Domain 4 – Refining and monitoring antithrombotic therapies

The objectives of this domain were to (a) systematically review and summarize the evidence for therapeutic monitoring of selected antithrombotic drugs in order to reduce the risk of complications or improve any outcomes in dogs and cats at risk for thrombosis, (b) develop clinical practice guidelines regarding antithrombotic monitoring, and (c) identify knowledge gaps in the field to guide future research.

Questions regarding the utility of therapeutic monitoring were developed for 6 different antithrombotic drugs or drug classes, including aspirin, clopidogrel, warfarin, unfractionated heparin, the low molecular weight heparins, and rivaroxaban, The majority of the literature pertaining to therapeutic monitoring of antithrombotic drugs was either performed in experimental animal models of disease or involved studies of drug pharmacokinetics and pharmacodynamics in healthy laboratory animals. There was a paucity of high level of evidence studies directly
addressing the PICO questions, which limited the strength of recommendations that could be provided.

The final guidelines recommend that therapeutic monitoring should be performed when using warfarin or unfractionated heparin in dogs and cats at risk of thrombosis, but also note that there is insufficient evidence to make strong recommendations for therapeutic monitoring of aspirin or low molecular weight heparin in dogs and cats at this time.

Guidelines for clopidogrel monitoring were not formulated at this time due to time constraints of the CURATIVE initiative, given the lack of literature directly addressing the PICO question, and the apparently safe, routine use of standard doses of clopidogrel as an antiplatelet drug in clinical practice.

The guidelines suggest that warfarin should not be used in dogs or in cats.

Sharp, C.R. et al. (2019) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 4—Refining and monitoring antithrombotic therapies. Journal of Veterinary Emergency and Critical Care, 29 (1), pp. 75-87. https://doi.org/10.1111/vec.12794 [This article can be accessed via RCVS Knowledge Library membership, click here]

Domain 5 – Discontinuation of anticoagulant therapy in small animals

This domain looked at appropriate approaches to use for small animal patients receiving antiplatelet or anticoagulant drugs and requiring temporary discontinuation of this therapy for the purposes of invasive procedures (e.g. surgery), and at decision-making for the complete discontinuation of anticoagulant medications. In addition, the most appropriate methodology for discontinuation of heparins was addressed.

The guidelines recommend that in patients at high risk for thrombosis, anticoagulation should not be discontinued for invasive procedures although they recommend discontinuing one agent if animals are receiving dual antiplatelet therapy.

In patients at low to moderate risk for thrombosis, consideration may be given for discontinuation of anticoagulation prior to invasive procedures.

In patients with thrombosis in whom the underlying cause for thrombosis has resolved, indefinite treatment with anticoagulant medication is not recommended. If the underlying cause is unknown
or untreatable, anticoagulant medication should be continued indefinitely.

Unfractionated heparin therapy should be slowly tapered rather than discontinued abruptly.

Brainard, B.M. et al. (2019) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE): Domain 5—Discontinuation of anticoagulant therapy in small animals. Journal of Veterinary Emergency and Critical Care, 29 (1), pp. 88-97. https://doi.org/10.1111/vec.12796 [This article can be accessed via RCVS Knowledge Library membership, click here]

Domain 6 – Defining rational use of thrombolytics

Sharp, C.R. et al. (2022) Update of the consensus on the rational use of antithrombotics and thrombolytics in veterinary critical care (CURATIVE) Domain 6: Defining rational use of thrombolytics. Journal of Veterinary Emergency and Critical Care, 32 (4), pp. 446– 470. https://doi.org/10.1111/vec.13227

Clinical applications

To illustrate the application of the Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines to the management of dogs and cats at risk of developing thrombosis the working group created a series of clinical cases that could be used to demonstrate how guideline recommendations could be applied.

The case studies provided are

A dog with immune mediated haemolytic anaemia
Aortic thrombosis in a dog with protein losing nephropathy
A dog receiving antithrombotic drugs that now requires surgery
A dog with sepsis
A dog with hyperadrenocorticism and pancreatitis
Initial presentation of a cat with cardiac disease
Subsequent presentation of a cat with cardiac disease and ATE

This paper also includes information on the drug formulations available and indicative costs,as provided by contributors from the US, Canada, the UK, and Australia.

Sharp, C.R. et al. (2019) Clinical application of the American College of Veterinary Emergency and Critical Care (ACVECC) Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines to small animal cases. Journal of Veterinary Emergency and Critical Care, 29 (2), pp. 121-131. https://doi.org/10.1111/vec.12804 [This article can be accessed via RCVS Knowledge Library membership, click here]

Other literature

Fox, P.R. et al. (2018) International collaborative study to assess cardiovascular risk and evaluate long‐term health in cats with preclinical hypertrophic cardiomyopathy and apparently healthy cats: The REVEAL Study. Journal of Veterinary Internal Medicine, 32 (3), pp. 930-943. https://doi.org/10.1111/jvim.15122
Jeffery, U., Staber, J. and LeVine, D. (2016) Using the laboratory to predict thrombosis in dogs: An achievable goal?. The Veterinary Journal, 215, pp. 10-20. https://doi.org/10.1016/j.tvjl.2016.03.027 [This article can be accessed via RCVS Knowledge Library membership, click here]
Winter, R.L. and Budke, C.M. (2017) Multicenter evaluation of signalment and comorbid conditions associated with aortic thrombotic disease in dogs. Journal of the American Veterinary Medical Association, 251 (4), pp. 438-442. https://doi.org/10.2460/javma.251.4.438 [This article can accessed via RCVS Knowledge Library Membership, click here]
Williams, T.P.E. et al. (2016) Aortic thrombosis in dogs. Journal of Veterinary Emergency and Critical Care, 27 (1), pp. 9-22. https://doi.org/10.1111/vec.12527 [This article can accessed via RCVS Knowledge Library Membership, click here]
Goggs, R. et al. (2014) Partnership on Rotational ViscoElastic Test Standardization (PROVETS): Evidence‐based guidelines on rotational viscoelastic assays in veterinary medicine. Journal of Veterinary Emergency and Critical Care, 24 (1), pp. 1-22. https://doi.org/10.1111/vec.12144 [This article can accessed via RCVS Knowledge Library Membership, click here]
Brainard, B. M. and Brown, A.J. (2011) Defects in coagulation encountered in small animal critical care. Veterinary Clinics of North America: Small Animal Practice, 41 (4), pp. 783-803. https://doi.org/10.1016/j.cvsm.2011.04.001 [This article can be accessed via RCVS Knowledge Library membership, click here]

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