Evaluation of Pimobendan In dogs with Cardiomegaly (EPIC) caused by preclinical degenerative mitral valve disease (MVD)

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EPIC sought to determine whether the administration of pimobendan to dogs with preclinical MVD would delay the onset of clinical signs.

EPIC was the largest prospective, blinded, placebo-controlled, randomised study to be conducted in veterinary cardiology to date. It involved 360 dogs recruited by 36 investigators across 11 countries in four continents.

The study took seven years to complete, and the lead investigators had the right to publish the results, regardless of the outcome. The results were presented at ACVIM Congress, Denver in June 2016 and were published in the Journal of Veterinary Internal Medicine in September 2016.

The study was terminated early after an interim analysis demonstrated a clear benefit in favour of pimobendan.

Patients

Client-owned dogs with stage B2 MVD¹ were recruited to EPIC using the following criteria:

  • ≥ 6 years of age
  • Between 4.1 and 15 kg
  • Evidence of preclinical MVD on auscultation (≥ grade 3/6 murmur) and echocardiography
  • Evidence of cardiomegaly on radiography and echocardiography

Intervention

180 dogs were randomised to receive pimobendan (Vetmedin®) at approximately 0.5 mg/kg/day.

Comparison

180 dogs were randomised to receive visually identical placebo.

Outcome

Primary endpoint

The primary endpoint was defined as the onset of left-sided CHF or cardiac-related death or euthanasia; dogs in the pimobendan group were significantly less likely to reach this endpoint (p=0.0038)

Administering pimobendan to dogs with preclinical MVD resulted in an extension of the median time to the primary endpoint of around 60% (Figure 1).

graph showing comparative effect of Pimobendan and a placebo
Figure 1: Median time to primary endpoint (onset of CHF or cardiac related death) in days

Another way to describe the results is to look at the risk of a dog reaching the primary endpoint at any time.

Dogs receiving pimobendan were around 33% less likely to go into CHF or suffer cardiac death at a given time than dogs receiving placebo; they therefore benefited from a risk reduction of around one third.

Secondary endpoint

The secondary endpoints were defined as ‘time to first event’ and ‘all-cause mortality’ (death from any cause).

Dogs receiving pimobendan had an extended time to first event (p=<0.0001) and lived longer (p=0.012) compared with dogs receiving placebo.

Safety

There were no significant differences in adverse event occurrence between the pimobendan and placebo groups.

Implications

The EPIC results are of significant clinical relevance, and challenge the prevailing view of preclinical MVD. Where previously a ‘watch and wait’ approach was appropriate in a dog with asymptomatic preclinical MVD, EPIC has demonstrated that many of these dogs will live longer and have a better quality of life if they are treated with pimobendan before the onset of clinical signs.

Based on the findings of EPIC, dogs with typical mitral valve murmurs (≥ grade 3/6) should be investigated to look for evidence of cardiomegaly. If cardiomegaly is identified, then EPIC provides evidence that the patient may benefit from receiving pimobendan without waiting for signs of CHF to develop.

Reference

  1. Atkins et al. (2009) J Vet Intern Med;23:1142–1150

Press Release

EPIC breakthrough at the RVC (4 October 2016)


Frequently Asked Questions

What does EPIC stand for?

EPIC stands for Evaluation of Pimobendan In dogs with Cardiomegaly (EPIC) caused by preclinical degenerative mitral valve disease (MVD). The EPIC study sought to determine whether the administration of pimobendan to dogs with preclinical MVD would delay the onset of clinical signs.

What was the study design?

EPIC was the largest prospective, blinded, placebo-controlled, randomised study to be conducted in veterinary cardiology to date. The study recruited 360 dogs at 36 veterinary clinics across 11 countries and four continents.

What were the inclusion criteria for the study?

The study recruited dogs from small-to-medium sized breeds in the preclinical stages of degenerative mitral valve disease. Each was assessed as being in the B2 stage of the condition with a heart murmur and some evidence of cardiac enlargement but with no clinical manifestations of heart failure.

The study excluded dogs that were at a more advanced stage and those receiving other forms of heart treatment.

How were these dogs assessed?

To confirm the presence of stage B2 degenerative mitral valve disease, the trial used two routine echocardiographic measurements, left atrial-to-aortic root ratio and left ventricular internal diameter in diastole. Additionally, a common radiographic measure of heart size, the vertebral heart sum (VHS) was used.

What were the results?

The EPIC study found pimobendan extended the asymptomatic period by an average of 15 months. Dogs that received the drug also lived significantly longer than those receiving a placebo.

Administering pimobendan to dogs with preclinical MVD resulted in an extension of the median time to the primary endpoint of around 60%.

Dogs receiving pimobendan benefited from a reduction of the risk of CHF or cardiac death by more than one third.

Why was the study stopped early?

After an interim analysis, the researchers decided to terminate the trial early as the result were so convincing and it was considered unethical to deny those dogs receiving the placebo the benefits seen in the treatment group.

How can first opinion practitioners identify those patients that will benefit from receiving the drug?

Based on the findings of EPIC, dogs with typical mitral valve murmurs (≥ grade 3/6) should be investigated to look for evidence of cardiomegaly. If cardiomegaly is identified, then EPIC provides evidence that the patient may benefit from receiving pimobendan without waiting for signs of CHF to develop.

Dogs identified with typical mitral valve murmurs can be further assessed using a common radiographic measure of heart size, the vertebral heart sum (VHS). An echocardiogram can also be used to confirm the diagnosis. If a vet is not a frequent user of this equipment, they may need refer the patient to a more experienced colleague to provide an accurate assessment.

Candidates for early treatment should not include those with B1 stage heart disease (i.e. those without cardiac enlargement) as there is no evidence of clinical benefit at this stage.

What can vets communicate to owners of dogs eligible for treatment?

Owners need to know there is no guarantee that their pet will get an extra 15 months of healthy life. It may be best to explain that a dog receiving the drug is more than a third less likely to go into heart failure at any given time than if it received no treatment.

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