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)

Abstract

Background: The renin-angiotensin-aldosterone system (RAAS), when chronically activated, is harmful and RAAS-suppressive drugs are beneficial in the treatment of congestive heart failure (CHF). Mineralocorticoid receptor antagonists are widely used in the treatment of CHF in people.

Hypothesis/objectives: To determine if a mineralocorticoid receptor antagonist (spironolactone) is beneficial and safe in CHF due to myxomatous mitral valve disease (MMVD) of varying severity, we hypothesized that, when combined with furosemide, a combination product (S+BNZ) containing the ACE inhibitor (ACE-I), benazepril, and spironolactone, would be superior to benazepril alone.

Animals: Five hundred and sixty-nine client-owned dogs, with MMVD and CHF (ACVIM Stage C) of ≤10-days' duration.

Methods: After initial stabilization, dogs were randomized into a positive-controlled, double-blind, multicenter trial, to receive furosemide plus S+BNZ or furosemide plus benazepril. The primary outcome variable was the percentage of dogs reaching cardiac endpoint before Day 360. Cardiac endpoint was defined as cardiac death or euthanasia, recurrence of pulmonary edema, necessity for nonauthorized cardiac drug(s) or a furosemide dosage >8 mg/kg/d.

Results: A significantly lower percentage of dogs treated with S+BNZ reached the primary outcome variable by Day 360 (OR = 0.56; 95% CI, 0.32-0.98; P = .04) and risk of dying or worsening from cardiac causes, was significantly reduced (HR = 0.73; 95% CI = 0.59-0.89, P = .002) vs benazepril alone. Adverse events, potentially associated with treatment, were rare and equal between groups.

Conclusion and clinical importance: The combination of S+BNZ is effective, safe, and superior to benazepril alone, when used with furosemide for the management of mild, moderate or severe CHF caused by MMVD in dogs.

Keywords: ACE inhibitor; MRA; RAAS; aldosterone breakthrough; mitral regurgitation.

FIGURE 1

A, Study sample flowchart: Efficacy sample (for cardiac endpoint at Day 360) and modified efficacy sample (for cardiac endpoint at Day 30, 90, 180, 270, 360). B, Study sample flowchart: Safety sample for time‐to‐event analysis, event being defined as: (1) cardiac endpoint; (2) all cause withdrawal

FIGURE 2

Diagram summarizing statistical methodology related to results from the BEnazepril Spironolactone STudy

FIGURE 3

Percentage of dogs with 95% CI remaining in study at Day 360 (*P = .04). BNZ, benazepril group; S+BNZ, spironolactone plus benazepril group

FIGURE 4

Percentages of dogs with 95% CI reaching the cardiac endpoint at each study visit (*Day 90, P = .03; Day 180, P = .04; Day 270, P = .01; Day 360, P = .04). BNZ, benazepril group; S+BNZ, spironolactone plus benazepril group

FIGURE 5

Kaplan‐Meier survival curves displaying the probability of not yet reaching the cardiac endpoint in the S+BNZ group (orange solid line) vs the BNZ group (gray dotted line). There were 284 dogs in the S+BNZ group and 285 dogs in the BNZ group at the outset (safety sample). Cross marks represent censored observations

FIGURE 6

Kaplan‐Meier survival curves displaying the probability of not being withdrawn for any cause in the S+BNZ group (orange solid line) vs the BNZ group (gray dotted line). There were 284 dogs in the S+BNZ group and 285 dogs in the BNZ group at the outset (safety sample). Cross marks represent censored observations

FIGURE 7

Percentage, risk difference, and the 95% CI for dog shaving at least 1 adverse event during the study, which was unrelated to cardiac condition (*P = .05). BNZ, benazepril group; S+BNZ, spironolactone plus benazepril group