EPIC: Evaluating Pimobendan in Cardiomegaly
Study Objective
To determine whether chronic oral administration of pimobendan in dogs with evidence of increased heart size secondary to preclinical myxomatous mitral valve disease (MMVD), can delay the onset of signs of congestive heart failure (CHF).
Professor Adrian Boswood
Royal Veterinary College
Veterinary Clinical Sciences
Hatfield, Hertfordshire, UK
Justification
- Currently there is no cardiac medication licensed for the treatment of preclinical MMVD.
- Pimobendan has been proven to reduce mortality as well as morbidity associated with congestive heart failure (CHF) due to MMVD and is licensed for the treatment of the clinical stages of MMVD in all countries where the study will be carried out.
- The combination of preload and afterload reduction in combination with inotropic support may result in a reduction in cardiac size and filling pressures in dogs with significant remodelling secondary to myxomatous mitral valve disease. These effects in dogs with preclinical MMVD could be anticipated to delay the onset of pulmonary oedema and clinical signs.
Study Design
- The study will be conducted as a double-blinded, randomised, placebo-controlled multi-centre field trial.
- The study will be conducted at 36 sites in 11 countries across four continents. The countries included are Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, United Kingdom and the United States.
- The study involves two treatment groups of 180 each, for a total of 360 dogs. Dogs will be randomly allocated to either the pimobendan or placebo group.
- The study will follow dogs to the primary endpoint (onset of clinical signs caused by left-sided congestive heart failure or cardiac related death).
Timeline
- A two-year recruitment phase will be followed by a three-year clinical phase.
- Recruitment period: 2010 - 2012
- Clinical phase: 2012 - 2015
Dosing Schedule
The pimobendan treatment group will receive a total daily dose of 0.4-0.6 mg/kg that will be administered twice daily, using a suitable number and split of chewable tablets.
Summary of Patient Inclusion Criteria
- Systolic heart murmur with maximal intensity over the mitral area.
- Echocardiographic evidence of myxomatous mitral valve disease defined as characteristic valvular lesions of the mitral valve apparatus in association with left atrial and left ventricular dilatation.
- Presence of mitral regurgitation on the colour Doppler echocardiogram.
- Radiographic evidence of cardiomegaly.
- Animals must be at least 6 years of age.
- Animals must have a body weight of 4.1 – 15 kg (9 – 33.1 lbs).
Primary Endpoint
- The primary endpoint is a composite of the development of left-sided congestive heart failure, or cardiac death.
- A dog will be considered to have left-sided congestive heart failure when there is radiographic evidence of cardiogenic pulmonary dyspnoea as indicated by an interstitial or alveolar pattern in conjunction with left sided cardiomegaly. In addition, the dog may also have a cough, dyspnoea, and an elevated heart rate without respiratory sinus arrhythmia.
Description of the statistical methods
- The aim of the study is to demonstrate superiority of the pimobendan treatment compared to placebo treatment.
- The primary variable for the evaluation will be the time period until the onset of clinical signs caused by left sided congestive heart failure or cardiac-related death.
- The statistical analyses for time to event will involve Kaplan-Meier analysis, log-rank test, and the Cox proportional hazard modelling.
Reflections on the power of the test/trial
- The length of the recruitment period is two years and the maximum length of follow-up five years. A minimum of three years follow-up will be granted following the accrual period.
- Results of prior studies have shown that the median time to onset of left-sided congestive heart failure in dogs with Stage B2 chronic myxomatous mitral valve disease is 27 months.
- Based on these assumptions 150 animals per group are sufficient to detect a difference in median time to onset of left-sided congestive heart failure with a power of 80%.