Clopidogrel (Plavix) and the results of the fat cat trial

CLOPIDOGREL (PLAVIX ©) AND THE RESULTS OF THE FAT CAT TRIAL

By Rebecca Malakoff, DVM, DACVIM (Cardiology)
www.angell.org/cardiology
cardiology@angell.org
617-541-5038 

Arterial thromboembolism (ATE) remains one of the most devastating and frustrating complications of cardiac disease in our feline patients.  Within the last decade, clopidogrel has widely entered use as a therapy to attempt to prevent ATE in at-risk cats.  This article will review the mechanism of action of clopidogrel, appropriate dosing, possible adverse effects, and potential survival benefits for patients who have suffered from an ATE. 

Clopidogrel bisulfate acts as a platelet aggregation inhibitor.  It is metabolized to an active compound which binds selectively to ADP receptors on platelets, irreversibly altering the receptor and inhibiting ADP binding at this site.  This mechanism of inhibition of platelet aggregation is different from that of aspirin (which is important to note, and may explain why the two drugs can work synergistically together).  Aspirin acetylates and inactivates COX-1 in platelets, thereby preventing formation of thromboxane A2.  Both drugs have effects which are irreversible, lasting the life of the platelet (7-10 days).

The antiplatelet effects and pharmacodynamics of clopidogrel administration to cats was studied in 2004 by Hogan et al.  In this study, the lowest dose studied was 18.75 mg (1/4 of a 75 mg tablet, chosen for practical purposes), and was determined to be as effective as higher doses in reducing platelet aggregation in cats.  Maximal effects were seen after 3 days, and platelet function returned to normal 7 days after stopping therapy.  This dose was then adopted as the typical dose for feline patients.

Clopidogrel use in cats appears to be well tolerated.  Drug references cite that some cats may vomit or develop anorexia (which may be diminished by giving the medication with food), but in the author’s experience this is rarely seen.  In human patients, the primary adverse effects of clopidogrel therapy are bleeding related, yet this remains relatively uncommon (in a major pre-clinical study, major bleeding occurred in approximately 2% of human patients treated).  Rashes and gastrointestinal effects (diarrhea) have been reported in people, and thrombotic thrombocytopenic purpura (TTP) is a rare adverse effect noted in human patients.

Although it is well tolerated, one of the challenges of clopidogrel therapy for veterinary patients can be difficulty in administration.  The tablets have a bitter taste, which many cats intensely dislike (even cats who take other medications without protest).  Putting the ¼ tablet in a gel cap or coated in canned food or another desirable food may help with administration.  The medication can be prepared as a liquid suspension by a reputable compounding pharmacy, but many cats find the taste unacceptable even with additional flavoring added.

In 2013, long anticipated results of the FAT CAT (Feline Arterial Thromboembolism: Clopidogrel vs. Aspirin Trial) were presented at the ACVIM conference.  This large scale multi-center prospective randomized trial sought to determine whether clopidogrel conferred any benefit in prevention of an arterial thromboembolism recurrence in cats compared to aspirin.  Cats that experienced a cardiogenic arterial thromboembolism event (CATE) and survived one to three months afterwards were eligible for enrollment.  Seventy-two cats were enrolled, and randomly assigned to receive either aspirin (81 mg PO every 3 days) or clopidogrel (18.75 mg PO daily) (36 cats in each group).  Median survival times were compiled for the primary endpoint (recurrent CATE event) , as well as for secondary endpoints of all-cause mortality, cardiac death, or study termination due to perceived adverse drug event. 

For the initial 12 month study period, the median survival time to the primary endpoint (recurrent CATE event) was 192 days in the aspirin group, and >365 days for the clopidogrel group (the median survival to CATE recurrence for the total study period for cats in the clopidogrel group was 443 days).  Median survival times for CATE or cardiac death combined were 128 days for the aspirin group, and 346 days for the clopidogrel group, and median survival times for all-cause mortality were 116 days in the aspirin group and 248 days in the clopidogrel group.  One cat from each study group had perceived adverse drug events necessitating removal from the trial (demonstrating that the majority of cats tolerated the study drugs well).

The FAT CAT study results indicate that clopidogrel was associated with a significant improvement in survival compared to aspirin for both the one year and total study period.  This is very exciting because it is the first prospective thromboprophylactic trial for CATE to demonstrate a significant survival benefit for any drug.  Studies involving clopidogrel and aspirin use in human patients, have shown some benefit to combined therapy for prevention of thromboembolism, and this may be an area of future research in veterinary patients. Although it is important that clients have realistic expectations (cats receiving clopidogrel can and do have ATE events, but our goal is to prolong symptom free time and/or decrease severity of events), the adoption of the use of clopidogrel in veterinary medicine, and the results of the FAT CAT study, provides us with an inexpensive, well-tolerated, medication regimen to effectively prevent thromboembolic events in our feline cardiac patients.

For more information, contact Dr. Rebecca Malakoff at rmalakoff@angell.org, send a message to the general Cardiology inbox at Cardiology@angell.org, or call the Cardiology service at 617-541-5038.

References

Hogan DF, Andrews DA, Green HW et al.  Antiplatelet effects and pharmacodynamics of clopidogrel in cats.  J Am Vet Med Assoc 2004;225(9): 1406-1411.

Hogan D, Fox P, Jacob K et al.  Analysis of the Feline Arterial Thromboembolism: Clopidogrel vs. Aspirin Trial (FAT CAT).  Proceedings: ACVIM 2013.