Compliance for canine mitral valve disease therapy just got easier

The early management of myxomatous mitral valve disease (MMVD) in dogs has historically been problematic. Diagnosis and staging without echocardiography were something very few of us had at our disposal several decades ago. Thus, it was difficult to justify early treatment with medications with little (or no) data. Today our understanding of MMVD and how to diagnose and treat has progressed.

Don’t wait…investigate the heart murmur at the earliest stages

Based on recent data, the American College of Veterinary Internal Medicine (ACVIM) consensus committee published updated guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs in 2019.¹ Among other revisions, the treatment recommendations for congestive heart failure (CHF) were updated. The quadruple therapy approach to CHF with a loop diuretic, pimobendan*, an angiotensin-converting enzyme inhibitor (ACEI), and the mineralocorticoid receptor antagonist (MRA), spironolactone, is now recommended for the latter stages of the disease complex.

Stage your MMVD patients

Figure 1.

Beyond the murmur intensity (grade I-VI/VI), these dogs should be staged based on objective, diagnostic parameters. A visual summary of the ACVIM guidelines staging is noted in Figure 1.

• Stage A dogs are at risk (including all small dogs) but do not currently have a mitral valve abnormality. An example of a stage A patient would be the classic MMVD poster-child, the cavalier King Charles spaniel. There are however many other at-risk breeds that should be identified. Stage B dogs do have a mitral valve abnormality. They usually have a systolic heart murmur and may have some degree of cardiac enlargement.
• Stage B dogs have a murmur but no significant evidence of left atrial enlargement or cardiomegaly. B2 denotes dogs with a left atrium to aorta ratio (LA:Ao) of >1.6 and a left ventricular end- diastolic diameter normalized for body weight (LVIDDn) >1.7. Because many veterinarians do not have access to echocardiography, the ACVIM does acknowledge that the vertebral heart score (VHS) > 11.5 with a systolic heart murmur > 3/6 (or 1 of the newly recognized mensuration systems that have been published) can substitute for quantitative echocardiography to identify stage B2. Such measurement techniques provide similar, if not specific, evidence of changing cardiac (left atrial) enlargement patterns. While there are multiple techniques demonstrated to show close proximity to echocardiographic derived measurements, where possible the echocardiogram remains the standard of choice for identifying these morphologic changes in the heart affected by MMVD.
• Stage C dogs have current or past clinical signs of congestive heart failure secondary to MMVD and evaluated.
• Stage D dogs are end-stage congestive heart failure patients. These dogs have either acute or past clinical signs of congestive heart failure and are refractory to the standard treatment. Usually, Stage D dogs require more than 8 mg/kg/day of furosemide or the equivalent dosage of torsemide (also known as torasemide or DEMADEX®, a registered trademark of Meda AB).

Quadruple therapy

The ACVIM endorsement of a quadruple therapy approach for CHF was a significant update to the consensus statement that was previously published in 2009. The use of spironolactone in CHF is an important part of that update. Its addition to traditional CHF therapy may not be for the reasons you were taught in school. Spironolactone is actually a powerful mineralocorticoid receptor antagnoist or blocker (MRA or MRB). The consensus panel agreed that a robust, broad-spectrum approach to suppression of the renin-angiotensin-aldosterone system (RAAS), including aldosterone inhibition, should be standard of care for CHF patients.

Why is control of the renin-angiotensin aldosterone system important?

One consequence of MMVD is activation of the RAAS. The RAAS is a primal, lifesaving mechanism meant to detect and adjust for changes in body homeostasis. For example, in situations where blood loss or dehydration occur, the kidneys detect decreased perfusion and release the enzyme renin. This begins the cascade causing vasoconstriction and retention of sodium and water. These functions work to expand blood volume and maintain organ perfusion. When the bleeding is stopped or dehydration is corrected, the cascade is deactivated. Short-term activation is a good thing—a great thing, particularly if the animal is experiencing blood loss or dehydration. This is not the case for the dog with MMVD. Long-term, chronic, unchecked activation of the RAAS occurs with MMVD because of decreased cardiac output. Negative consequences occur due to excess production of angiotensin II and aldosterone. When this system is activated chronically, retention of sodium and water, chronic vasoconstriction, and cardiac remodeling or fibrosis result (see Figure 2).

Figure 2.

Why aren't ACEIs enough to suppress RAAS?

It was long-believed that inhibition of angiotensin II production (with the use of ACEIs such as benazepril or enalapril) would benefit the patient by reducing overall angiotensin II concentration and by preventing the downstream production of aldosterone. While this is true in some cases, aldosterone breakthrough (ABT) occurs in approximately 30 to 40% of dogs on ACEIs.² Because there are non-ACE-dependent pathways of aldosterone production and possibly some negative feedback mechanisms at play, we now know that ACEIs alone are not enough. In fact, broadspectrum inhibition of this deleterious system with a combination of spironolactone and benazepril (CARDALIS™) resulted in better outcomes for patients in a recently completed clinical trial.³ As with so many diseases that we treat in veterinary medicine, a broad-spectrum approach is often the path to success.

Compliance is key

If we know that quadruple therapy is best for the patient, then what’s the problem? If you are a seasoned veterinary practitioner, you’re aware of the inevitable challenges associated with polypharmacy. With more drugs comes poor compliance which leads to less effective clinical outcomes and lowered client satisfaction.

In early 2021, Ceva Animal Health, LLC came to market with a solution to the issue of polypharmacy and compliance in the cardiac patient. CARDALIS™ is a combination of spironolactone and benazepril hydrochloride developed to provide for a more complete RAAS blockade. Available in a convenient, once-per-day, flavored, chewable tablet, CARDALIS™ was found to be safe and effective by the FDA and is approved for mild, moderate, and severe congestive heart failure (CHF) due to mitral valve disease in dogs.

CARDALIS™ provides half of the ACVIM quad therapy recommendation for CHF due to MMVD in dogs (see Figure 3).

Figure 3.

I would expect a convenient, chewable option to provide the pet owner and mitral valve disease patient with a more pleasant, effective, and superior medication experience. Improved compliance results in a longer life, better quality of life, and increased client satisfaction. Having an alternative to human generics in the form of an FDA-approved, once-daily medication with proven safety and efficacy data provides the practitioner with peace of mind when prescribing for one of their most vulnerable (and difficult to medicate) patient populations.³ The small, chewable tablets were found to be palatable and well accepted in 87.6% of patients in the pivotal efficacy trial for FDA approval for CARDALIS™.³ The yeast-based, beef flavoring contains no beef protein and would not be expected to create a beef-allergy challenge for food-allergic patients.

To support the product, Ceva is providing the practicing veterinarian with numerous virtual educational experiences at cevaconnect.com as well as numerous live, continuing educational events throughout 2021. Additional tools, including client communication aids and the free CARDALIS™ resting respiratory rate app, offer the practitioner a variety of helpful resources (see Figure 4).

Figure 4.

References

1. Keene, BW, Atkins, CE, Bonagura, JD, et al. ACVIM consensus guidelines for the diagnosis and treatment of myxomatous mitral valve disease in dogs. J Vet Intern Med. 2019; 33: 1127–1140. https://doi.org/10.1111/jvim.15488
2. Ames MK, Atkins CE, Eriksson A, Hess AM. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. J Vet Cardiol. 2017 Jun;19(3):218-227. doi: 10.1016/j. jvc.2017.03.001. Epub 2017 May 31. PMID: 28576479.
3. Coffman M, Guillot E, Blondel T, et al. Clinical efficacy of a benazepril and spironolactone combination in dogs with congestive heart failure due to myxomatous mitral valve disease: The BEnazepril Spironolactone STudy (BESST). J Vet Intern Med. 2021; 1– 15. https://doi.org/10.1111/jvim.16155
4. Sayer, M., Atkins, C, Fujii, Y, Adams, et al. Acute Effect of Pimobendan and Furosemide on the Circulating Renin-Angiotensin-Aldosterone System in Healthy Dogs. J Vet Intern Med. 2009; 23: 1003-1006. https://doi.org/10.1111/j.1939-1676.2009.0367.x

*In 2019, the ACVIM published new guidelines recommending a quadruple therapy approach for the treatment of CHF in dogs. The safety and efficacy of CARDALIS™ has not been investigated with pimobendan.

Full prescribing information at www.cardalis.com

Important Safety Information: Do not administer in conjunction with non-steroidal anti-inflammatory drugs (NSAIDs) in dogs with renal insufficiency. Do not use in dogs with hypoadrenocorticism (Addison's disease), hyperkalemia or hyponatremia. Do not use in dogs with known hypersensitivity to ACE inhibitors or spironolactone. The safety and effectiveness of concurrent therapy of Cardalis™ with pimobendan has not been evaluated. The safety of Cardalis™ has not been evaluated in pregnant, lactating, breeding, or growing dogs. Cardalis™ administration should begin after pulmonary edema is stabilized. Regular monitoring of renal function and serum potassium levels is recommended. Common side effects from a field study include anorexia, vomiting, lethargy, diarrhea, and renal insufficiency

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