Managing Congestive Heart Failure Secondary to Myxomatous Mitral Valve Disease

In the literature

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;35(4):1673-1687.

The Research …

Chronic activation of the renin–angiotensin–aldosterone system (RAAS) exerts harmful effects on the cardiovascular system, including myocardial remodeling, increased peripheral vascular resistance, and pathologic retention of sodium and water.^1,2 Previous prospective, placebo-controlled studies demonstrated that blockade of the RAAS is beneficial for management of congestive heart failure secondary to myxomatous mitral valve disease (MMVD; ACVIM stage C).^3-5 

This study (ie, BEnazepril Spironolactone STudy [BESST])* investigated the efficacy of an ACE inhibitor combined with an aldosterone antagonist versus an ACE inhibitor alone. Dogs with ACVIM stage C MMVD were enrolled, and all subjects received furosemide during the study period. Dogs were randomly assigned to either a combination treatment (benazepril and spironolactone) or an ACE inhibitor (benazepril) only group. Time to primary cardiac endpoint―defined by cardiac death/euthanasia, recurrence or worsening of pulmonary edema, development of cardiogenic ascites, and/or worsening or new cardiac clinical signs, necessitating therapy with a nonauthorized cardiac drug or furosemide (>8 mg/kg every 24 hours)―was assessed over 360 days.

Risk for sudden cardiac death or worsening of cardiac status was reduced by 27% in dogs receiving the combination treatment. Severe adverse effects were rare and did not significantly differ between treatment groups. 

Pimobendan, a positive inotrope and balanced vasodilator, was not permitted by the study design. Pimobendan has been demonstrated to significantly improve survival in dogs with MMVD.^6-8 It is unclear whether the apparent benefit conferred by the combination of benazepril and spironolactone would remain significant in the context of pimobendan therapy.  

The optimal dosing strategy for ACE inhibitor therapy in dogs is unknown. Ranges of 0.25 to 0.5 mg/kg PO every 12 to 24 hours have been published, with some assertion that a 12-hour interval and a total daily dose of >0.5 to 1 mg/kg are most clinically effective.^9-12 For the BESST study, dogs in both the combination therapy and ACE inhibitor alone groups received a mean total daily benazepril dose of 0.37 and 0.36 mg/kg PO, respectively. The potential benefit of ACE inhibitor therapy may not have been fully realized. 

Attempts to maximize RAAS inhibition are complicated by chronobiology and genetic polymorphisms.^2,13,14 Chronobiology refers to the concept of neurohormonal circadian rhythms. There is evidence in dogs that renin activity is synchronized by the timing of meals¹⁵; therefore, the timing of drug administration may have clinical implications.¹² Genetic polymorphisms that affect the function of the RAAS cascade have been identified, and a higher percentage of affected dogs exhibit evidence of aldosterone breakthrough following treatment with an ACE inhibitor compared with polymorphism-negative dogs.¹³ These findings indicate that aldosterone antagonism may be an important part of optimal RAAS blockade. Polymorphism is overrepresented in Cavalier King Charles spaniels,¹⁴ which comprised ≈10% of the BESST sample population.

… The Takeaways

Key pearls to put into practice:

• Combination therapy with benazepril and spironolactone is safe and more effective than benazepril alone in dogs receiving furosemide for management of ACVIM stage C MMVD.

• A combination product is manufactured as fixed-dose tablets containing 2.5/20, 4/40, or 10/80 mg of benazepril/spironolactone; this may provide convenience for the pet owner, but there is some loss of flexibility in dosing. Benazepril and spironolactone can be administered separately to provide an optimal dose (in accordance with ACVIM guidelines).⁹

• Pimobendan remains vital for management of MMVD; RAAS inhibition should be used in addition to (rather than as a replacement for) pimobendan in dogs that progress to ACVIM stage C.

*The study was funded by Ceva Santé Animale.