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The EPIC Study: The effect of pimobendan in dogs | VETgirl Veterinary Continuing Education Blog

In today's VETgirl online veterinary continuing education blog, we review an "EPIC" study called "Effect of Pimobendan in Dogs with Preclinical Myxomatous Mitral Valve Disease and Cardiomegaly: The EPIC Study – A Randomized Clinical Trial" by Boswood et al. This was a huge study that was conducted at dozens of different institutions (both academia and private practice) around the world and was undertaken by dozens of cardiologists.

Myxomatous mitral valve disease (MMVD) is the most common form of heart disease in dogs and can result in progressive left-sided cardiac volume overload and eventual congestive heart failure (CHF). The disease is classified in four stages:

A: Breeds predisposed to the disease but no phenotypic disease yet
B: Dogs with evidence of disease but no clinical signs of CHF
C: Dogs with clinical signs of CHF
D: Dogs with clinical signs of CHF refractory to treatment

Stage B is further subdivided into:
B1: Dogs with no evidence of heart enlargement
B2: Dogs with evidence of heart enlargement

There are currently no therapies available that have demonstrated a definitive, universally-accepted benefit for dogs with stage B2 disease (including the investigations of use of enalapril in asymptomatic MMVD). Use of pimobendan, an inodilator (a positive inotrope and vasodilator) has been shown to improve both quality and quantity of life in dogs with stage C disease, but its use in stage B2 disease has not been previously evaluated.

So, Boswood and a huge number of cardiologists throughout the world wanted to evaluate whether administration of pimobendan to dogs with stage B2 MMVD would delay the onset of CHF or cardiac death. In this clinical trial (which first began in 2009), the authors and researchers included all dogs between 4.1 and 15 kg that had a physical exam and echocardiographic evidence of stage B2 MMVD. Specific inclusion criteria included radiographic criteria of a VHS > 10.5 and echocardiographic findings of a LA/Ao (left atrial-to-aortic ratio) of  ≥ 1.6 and a LVIDDN ≥ 1.7 (Echocardiographically-derived left ventricular internal diameter in diastole normalized to body weight). Dogs were excluded if they had significant systemic disease, cardiac disease other than MMVD, pulmonary hypertension with a RV-RA PG > 65 mm Hg (Echocardiographically-derived right ventricular-to-right atrial pressure gradient as surrogate measure of pulmonary artery pressure), or any dogs who had received any cardiac medication for > 14 days duration at any time or within 30 days of the enrollment in the trial. That said, the use of bronchodilators, corticosteroids, cough suppressants, and appetite stimulants were NOT criteria for exclusion and were permitted in this prospective, blinded, randomized, placebo-controlled study.

In this study, a total of 354 dogs were included. 178 dogs were placed in the pimobendan group, while 176 dogs were in the placebo group. All of the dogs in this study received a physical examination, blood pressure measurement, echocardiography, thoracic radiography, and clinicopathologic monitoring (including hematology and serum biochemistry) prior to enrollment. The median age of dogs was 9 years, and there was no differences in baseline variables except body condition score (BCS) and breed distribution. In the treatment group, pimobendan was administered at a dose of 0.4-0.6 mg/kg/day, divided into twice daily dosing. In this study, the primary endpoint was defined as the development of left-sided CHF (based on clinical signs and radiographic findings), euthanasia (cardiac disease-related), or cardiac death.

So, what did this study find? First, this study was terminated early at 3.5 years (the original design was to conduct the study for a 5 year period) when results of the planned interim analysis indicated “convincing evidence of efficacy” of the trial drug, pimobendan. Almost 46% of dogs (n=162) reached the primary endpoint, with 74/178 (41.6%) in pimobendan group (59 CHF) and 88/176 (50%) in the placebo group (76 CHF). These proportion of dogs reaching the primary endpoint in this study was NOT significantly different between groups. However, there was a satistically significant difference in the median time period to the primary endpoint between the pimobendan group (1228 days) as compared to the placebo group (766 days). There was also a significant difference in the median time period to the "first event," with the pimobendan group being 640 days as compared to the placebo group of 406 days.

When looking at all-cause mortality, the pimobendan group comprised of 46.4%, while the placebo group comprised 57.2%. The median time to all cause mortality was 1059 days in the pimobendan group as compared to 902 days in the placebo group. In patients with an increased VHS, lower systolic blood pressure, and higher resting heart rate, there was an associated worse outcome.

Why is this study important? This clinical trial is the first of any kind to demonstrate a clear benefit of pimobendan therapy for dogs with stage B2 MMVD. Pimobendan reduced the risk of reaching the primary endpoint by 36% with a 462 day (15 month) delay in the onset of the primary endpoint (CHF or death). The majority of this benefit was attributable to a delay in the onset of CHF, specifically. The termination of the trial following the interim analysis due to demonstration of a clear benefit of pimobendan therapy is an important indicator of the strength of the data/results, as requirements for terminating trials at interim analysis are quite stringent. The trial also demonstrated worse outcomes for those patients with lower resting blood pressure which has not been previously reported (none of these dogs were technically hypotensive however). A major limitation of the study is its funding by the manufacturer of the trial drug/pimobendan.

So, what can we take from this VETgirl blog?

This is a hugely important study for veterinary cardiology, and veterinary medicine at large. The key precautions for general practitioners to take following their digestion of the results of the study are:

1) Although radiographic VHS > 10.5 was one inclusion criteria in this trial, it is likely in all parties’ (veterinarians, pets, pet owners) best interests that the full scope of cardiac imaging (echocardiography) be performed to confirm the appropriateness before prescribing pimobendan for dogs with stage B2 MMVD. A wide range of variability in radiographic quality, technique, and expertise of interpretation is expected to exist among veterinarians that could lead to prescription of pimobendan for dogs who may in fact not yet have stage B2 MMVD.

2) This trial DOES NOT support the use of pimobendan in dogs with stage B1 MMVD, nor does it support the use of pimobendan in asymptomatic dogs with mitral valve-associated systolic heart murmurs alone (regardless of intensity) who have NOT undergone cardiac imaging of any kind to enable classification as stage B1 vs B2.

3) Although the study was funded by the manufacturer of pimobendan, the results do not appear equivocal, but rather quite the opposite. Nonetheless, an independent clinical trial of similar methodology would eliminate the confounding factor of bias.

You can also find great information at their website here.

So, before you reach for pimobendan in that patient with a heart murmur, take the time to stage it, take radiographs, measure a blood pressure and VHS, recommend echocardiography (by a board-certified veterinary cardiologist) and work with the pet owner and cardiologist to help your patients with MMVD live longer!

Abbreviations:
MMVD: Myxomatous mitral valve disease
CHF: Congestive heart failure
Kg: Kilograms
VHS: Radiographically-derived Vertebral Heart Sum
LA/Ao: Echocardiographically-derived left atrial-to-aortic ratio
LVIDDN: Echocardiographically-derived left ventricular internal diameter in diastole normalized to body weight
RV-RA PG: Echocardiographically-derived right ventricular-to-right atrial pressure gradient as surrogate measure of pulmonary artery pressure
Mg: Milligrams
BCS: Body condition score

References:
1. Boswood A, Haggstrom J, Gordon SG, et al. Effect of pimobendan in dogs with preclinical myxomatous mitral valve disease and cardiomegaly: the EPIC study – a randomized clinical trial. J Vet Intern Med 2016;30:1765-1779.

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