Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study-A Randomized Clinical Trial

Abstract

Background: Pimobendan is effective in treatment of dogs with congestive heart failure (CHF) secondary to myxomatous mitral valve disease (MMVD). Its effect on dogs before the onset of CHF is unknown.

Hypothesis/objectives: Administration of pimobendan (0.4-0.6 mg/kg/d in divided doses) to dogs with increased heart size secondary to preclinical MMVD, not receiving other cardiovascular medications, will delay the onset of signs of CHF, cardiac-related death, or euthanasia.

Animals: 360 client-owned dogs with MMVD with left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7, and vertebral heart sum >10.5.

Methods: Prospective, randomized, placebo-controlled, blinded, multicenter clinical trial. Primary outcome variable was time to a composite of the onset of CHF, cardiac-related death, or euthanasia.

Results: Median time to primary endpoint was 1228 days (95% CI: 856-NA) in the pimobendan group and 766 days (95% CI: 667-875) in the placebo group (P = .0038). Hazard ratio for the pimobendan group was 0.64 (95% CI: 0.47-0.87) compared with the placebo group. The benefit persisted after adjustment for other variables. Adverse events were not different between treatment groups. Dogs in the pimobendan group lived longer (median survival time was 1059 days (95% CI: 952-NA) in the pimobendan group and 902 days (95% CI: 747-1061) in the placebo group) (P = .012).

Conclusions and clinical importance: Administration of pimobendan to dogs with MMVD and echocardiographic and radiographic evidence of cardiomegaly results in prolongation of preclinical period and is safe and well tolerated. Prolongation of preclinical period by approximately 15 months represents substantial clinical benefit.

Keywords: Asymptomatic; Echocardiography; Endocardiosis; Heart failure; Mitral regurgitation; Prevention; Treatment; Vertebral heart sum.

Figure 1

A flow chart indicating the outcome of 360 dogs randomized in the study. Where 3 numbers appear in red in the diagram, they represent the outcome of dogs in each subgroup with respect to the all‐cause mortality analysis. They indicate, in the order in which they appear, dogs known to have died/dogs known to be alive/dogs lost to follow‐up. ACM, all‐cause mortality, ITT; intention to treat; PP, per protocol; CHF, congestive heart failure.

Figure 2

Kaplan‐Meier survival curves plotting the estimated percentage of dogs in each group in the per‐protocol population that have not yet met the primary endpoint (congestive heart failure or cardiac death), against time. There were 178 dogs in the pimobendan group and 176 dogs in the placebo group at the outset. CI, confidence interval; NA, not able to calculate.

Figure 3

Kaplan‐Meier survival curves plotting the estimated percentage of dogs in each group in the per‐protocol population that have not yet experienced an event (defined as having reached the primary endpoint, undergone euthanasia or died for a noncardiac reason, had chronic medication initiated (Table 1 or Table 2), had a congestive heart failure endpoint that was not verified by the endpoint committee, the owner became noncompliant with study procedures, or the dog was withdrawn from the study by the owner or investigator), against time. There were 178 dogs in the pimobendan group and 176 dogs in the placebo group at the outset. CI, confidence interval.