MT20-007 Synergistic inhibitory effects of clopidogrel and rivaroxaban on platelet function and platelet-dependent thrombin generation in cats (An EveryCat-funded research project)

Principal Investigators: Joshua Stern, Ronald Hak Long Li; University of California-Davis J Vet Intern Med. 2023 May 19. DOI: 10.1111/jvim.16727.  PMID: 37208839.

Hypertrophic cardiomyopathy (HCM) is a common condition in cats characterized by the thickening of the heart’s left ventricle. One of the complications associated with HCM is cardiac (left atrial) generated clot leading to ATE (CATE), which occurs when a blood clot forms in the heart and blocks an artery, causing tissue damage. CATE has a high mortality rate.

Cats with HCM are more prone to blood clot formation due to an enlarged left atrium and increased risk of blood stasis. Currently, there is no universal standard treatment for CATE, but the use of an antiplatelet drug called clopidogrel is recommended to prevent blood clot formation. Studies have shown that clopidogrel alone may not be fully effective in preventing CATE recurrences in cats. Some cats may be resistant to clopidogrel due to genetic factors. To address this, a combination approach called dual antithrombotic treatment (DAT) is being used. DAT involves using both clopidogrel and another anticoagulant drug called rivaroxaban to enhance the prevention of blood clot formation. Rivaroxaban is a newer oral anticoagulant that inhibits a specific factor involved in clotting.

In this EveryCat- funded study, nine apparently healthy 1-year-old cats were selected from a research colony. 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 washout periods between treatments.

Blood samples in cats were tested for platelet aggregation and activation, and for actuation of the clotting system (thrombin generation).

The authors found that clopidogrel was able to reduce platelet aggregation. However, only DAT significantly decreased the number of activated platelets, modulated platelet activation in response to thrombin, dampened thrombin generation potential, and delayed maximum reaction velocity in thrombin generation. Rivaroxaban alone actually increased platelet activation (though likely had marked inhibitory effects on other coagulation parameters).

This data shows that dual therapy is more effective than clopidogrel alone, and that rivaroxaban alone actually increases platelet activation, an effect mitigated by the addition of clopidogrel. This suggests that dual therapy may be superior to either therapy alone.

It is increasingly understood that rivaroxaban is a viable option for the prevention of CATE in cats. Major drawbacks have been the increased cost and higher risk of bleeding compared to clopidogrel, however bleeding risks are still low and costs generally come down with time. An advantage has been the possibility of a more potent anti-clotting effect and the more consistent efficacy of the drug. This research shows that even in animals receiving rivaroxaban there is still a utility to clopidogrel therapy.

There were some limitations to this research. The most significant is the classic issue in feline thromboembolism research, the use of surrogate endpoints. In an ideal world, the researchers would demonstrate that a therapy or combination of therapies decrease the risk of thrombotic events ideally in a primary prevention strategy. This is extremely difficult due to the large numbers of cats needed to be followed up for long periods of time, especially in situations like this where the differences are likely to be small (though still clinically relevant). As such, the use of surrogates such as changes in measures of platelet function is needed, though less than ideal.

Further work into dual anticoagulation is actively being pursued by many authors, and this is an area where further information is no doubt forthcoming.

Summary prepared for EveryCat Health Foundation – MK