Published in March 2017
By Rebecca Quinn, DVM, DACVIM (Internal Medicine and Cardiology)
The first published studies evaluating pimobendan in animal models of human cardiac disease were published in the mid-1980s. These studies convincingly demonstrated pimobendan’s effective use in a range of cardiac disease, including myocardial ischemia, cardiomyopathy, and heart failure.1,2 From the start, pimobendan was identified as an “inodilator,” unique in its abilities to concurrently improve cardiac contractility while also alleviating cardiac workload via vasodilation.3 While initial studies in human clinical trials suggested pimobendan successfully treated patients with severe chronic congestive heart failure, the human community moved away from this therapy after additional research demonstrated that pimobendan use may be associated with increased mortality rates and sudden death.4, 5, 6
The veterinary community persisted, especially as more and more clinically based trials provided strong evidence that pimobendan use in our cardiac patients offered both improved quality of life and increased survival rates. Specific studies evaluating pimobendan use in dogs with pre-clinical dilated cardiomyopathy and valvular heart disease with congestive heart failure provided invaluable information supporting the use of pimobendan in these specific patient populations. 7, 8, 9, 10 And now, decades after the first publications on pimobendan use were released, we finally have strong evidence supporting the use of pimobendan therapy in canine patients with pre-clinical valvular heart disease.
The EPIC study began in 2010, was completed in 2015, and published in 2016. 11 The goal of the study was to evaluate the use of pimobendan in dogs with asymptomatic valvular heart disease, specifically those assigned as ACVIM Consensus Class B2 (evidence of cardiac remodeling without clinical signs of disease). 12 The study was prospective, multicenter, and blinded; the study included dogs over 6 years of age, weighing ≥ 4.1 and ≤15.0 kg, and with ≥3/6 systolic heart murmurs. Again, these dogs also had evidence of Class B2 Consensus chronic valvular heart disease, indicating left atrial and ventricular enlargement without sings such as cough or labored breathing. Dogs were excluded if they had evidence of significant systemic disease, arrhythmias, current or previous congestive heart failure, moderate to severe pulmonary hypertension, or if they had been treated with a variety of other cardiac therapies (for example angiotensin converting enzyme inhibitors, beta blockers, or positive inotropes to name a few). Dogs underwent a series of diagnostics, including thoracic radiographs and echocardiogram. The primary endpoint of the study was the development of congestive heart failure, euthanasia for cardiac reasons, or cardiac death.
The EPIC study included 354 dogs. The majority of the patients were Cavalier King Charles Spaniels (45.5%), and the mean age was 9.0 years. The dogs included in the study were randomly assigned to receive either placebo (176) or pimobendan (178); the pimobendan dose ranged from 0.2 to 0.3 mg/kg by mouth twice a day. The dogs receiving placebo had a median survival to the primary endpoint of 766 days, while the dogs receiving pimobendan had a median survival of 1,228 days. Additionally, 158/176 placebo dogs and 130/178 pimobendan dogs experienced a primary end point event. Further analysis indicated that median time to the first event in placebo dogs was 406 days, while the pimobendan dogs showed an improved time of 640 days. These results demonstrate that dogs who received pimobendan therapy lived longer, were less likely experience congestive heart failure or cardiac death, and have a delayed onset of cardiac clinical signs should they occur.
The EPIC results are very promising when assessing the use of pimobendan in ACVIM Consensus Class B2 valvular heart disease; the study results are published in depth, with additional information provided regarding each patient group. The study discussion highlights very interesting points regarding the use of pimobendan in preclinical valvular heart disease, with a straightforward conclusion regarding how to utilize this valuable information. It is of interest to note that an interim analysis was completed during the study, and that the benefits of pimobendan were so clear that the project was concluded early. From the information gathered, dogs with specific diagnostic results are likely to benefit from pimobendan therapy: those with radiographic vertebral heart scores ≥10.5, left atrial:aortic (LA:Ao) of ≥1.6, and echocardiographic left ventricular internal diameter (normalized to body weight) of ≥ 1.7.
As with all new information, it is important to understand details and apply the information presented by the EPIC study cautiously. While the study brings forth new information that will clearly benefit our patients, we must be cautious of our use of pimobendan and take care not to overtreat patients unlikely to benefit from this therapy.
For more information, please contact Angell’s Cardiology Service at 617-541-5038 or firstname.lastname@example.org.
- Verdouw et al. Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties. Eur J Pharmacol. July 1986;126(1-2):21-30
- vanMeel et al. Pimobendan increases survival in cardiomyopathic hamsters. J Cardiovasc Pharmacol. March 1989;13(3)508-509.
- Pouler et al. Effects of pimobendan (UD-CG 115) on the contractile function of the normal and postischemic canine myocardium. J Cardiovasc Pharmacol. January 1988;11(1):100-106.
- Renard et al. Pimobendane (UD-CG 115 BS) in chronic congestive heart failure. Short-term and one-month effects of a new inotropic vasodilating agent. Chest. June 1988;93(6):1159-1164.
- Komajda M. Treatment of chronic heart failure: current views. Arch Mal Coeur. April 1995;88(Supp 4):603-606
- Hagemeijer F. Calcium sensitization with pimobendan: pharmacolog, haemodynamic improvement, and sudden death in patients with chronic congestive heart failure. Eur Heart J. 1993;14(4):551-566.
- Fuentes et al. A double blind, randomized, placebo-controlled study of pimobendan in dogs with DCM. JVIM 2002;16:255-261.
- Summerfield et al. Efficacy of pimobendan in the prevention of CHF or sudden death in Doberman Pinchsers with preclinical DCM (The PROTECT Study). JVIM 2012;26:1337-1349.
- Haggstrom et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with CHF caused by naturally occurring MMVD: the QUEST study. JVIM 2008;22:1124-1135.
- Boswood A. Current use of pimobendan in canine patients with heart disease. Vet Clin Small Animal. 2010;40;571-580.
- Boswood et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study – a randomized clinical trial. JVIM. November 2016;30(6):1765-1779.
- Atkins et al. Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. JVIM 2009;23:1142-1150.