Efficacy of pimobendan in the prevention of congestive heart failure or sudden death in Doberman Pinschers with preclinical dilated cardiomyopathy (the PROTECT Study)

Abstract

Background: The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported.

Hypothesis: That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival.

Animals: Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America.

Methods: The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint.

Results: The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441-1152 days) versus the placebo group (441 days, IQR 151-641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491-1531 days) versus the placebo group (466 days, IQR 236-710 days) (log-rank P = .034).

Conclusion and clinical importance: The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.

Fig. 1

A flow chart indicating the outcome for the 76 dogs enrolled in the study.

Fig. 2

Kaplan Meier survival curves plotting the estimated percentage of dogs in each group that have not yet met the primary endpoint, against time. IQR, interquartile range

Fig. 3

Kaplan Meier survival curves for the all-cause mortality analysis, plotting the estimated percentage of surviving dogs in each group, against time. MST, median survival time; IQR, interquartile range.

Fig. 4

A forest plot showing the hazard ratio and 95% confidence intervals associated with variables considered in the univariable analyses with time to the primary endpoint (congestive heart failure or sudden death) as the dependent variable. Circles represent the hazard ratio and the horizontal bars extend from the lower limit to the upper limit of the 95% confidence interval of the estimate of the hazard ratio. CHF, congestive heart failure; SCD, sudden cardiac death; LVIDDN, normalized left ventricular internal diameter in diastole; LVIDSN, normalized left ventricular internal diameter in systole; VPCs, ventricular premature complexes; /10 indicates that the hazard ratio is for a 10-unit change in the variable of interest; /1000 indicates that the hazard ratio is for a 1000-unit change in the variable of interest; ×10 indicates that the hazard ratio is for a 0.1-unit change in the variable of interest.

Fig. 5

The number of VPCs on the 24-hour ECG before and approximately 1 month after the initiation of treatment in the group receiving pimobendan (A) and the group receiving placebo (B). Differences were not significant in either group. VPC, ventricular premature complex. Four datapoints do not appear on the logarithmic scale when the VPC number was zero. These are 2 dogs in the pimobendan group pretreatment, 1 pimobendan dog post treatment, and 1 placebo dog pretreatment.

Fig. 6

The change in left ventricular diameter occurring within the first 2 months of the study for dogs in which paired observations were available (73 dogs, 38 receiving pimobendan, and 35 receiving placebo). The change in systolic diameter is illustrated in Figure 6A and the change in diastolic diameter in Figure 6B. LVIDS, left ventricular internal diameter in systole; LVIDD, left ventricular internal diameter in diastole.