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HAMLET and Evaluation of Pimobendan in Dogs with Cardiomegaly (EPIC)

Challenge       

Whilst there are a number of disease processes that affect the canine heart, mitral valve disease (MVD) is by far the most common. The mitral valve is situated in the left side of the heart, between the left atrium and the left ventricle. The normal function of the mitral valve is to ensure that blood flows in the right direction. It acts as a one-way valve, allowing blood to move from the left atrium to the left ventricle and, when the left ventricle contracts, the mitral valve also ensures that blood is pumped forwards to the body by blocking any movement backwards into the left atrium.

When dogs are affected by MVD, for reasons that are not fully understood, the valve tissue degenerates, becoming distorted and unable to fully close. Functionally, this means that when the left ventricle contracts, some blood leaks through the misshapen valve, moving backwards into the left atrium. This leak causes an audible murmur, which can be detected by listening to the heart with a stethoscope as part of a clinical examination.

MVD is a progressive disease and gets worse with time. However, the rate at which the disease advances varies a great deal between individuals. In a majority of dogs, this rate is slow and not all individuals will develop symptoms within their lifespan. In cases where the disease does progress, MVD may bring about secondary changes to the shape, size and function of the heart. Dogs with advancing disease may go on to develop congestive heart failure, showing symptoms such as an increased respiratory rate when resting, breathlessness, coughing and a reduced tolerance for exercise. Dogs that are in congestive heart failure are very likely to die as a result of their heart condition.

Solution      

The HAMLET Study: In the early stages of MVD, prior to the onset of heart failure, a cardiac ultrasound scan is required to confirm a diagnosis of MVD. In these asymptomatic dogs, evidence of an increased heart size on the cardiac ultrasound scan is interpreted as a sign that their MVD is more advanced and used as the basis of therapeutic decision making. When ultrasound measurements exceed certain limits, affected dogs are now routinely treated with a drug called pimobendan. When given daily, this treatment is associated with a reduction in the risk of developing congestive heart failure. Chronic treatment with pimobendan has been shown to delay the onset of congestive heart failure, extending the amount of time that a dog lives without the symptoms of disease.

In first opinion practice, asymptomatic dogs often need to be referred to a cardiac specialist in order to ensure that accurate ultrasound measurements are obtained. This can prove restrictive, as many dogs are unable to undergo the recommended tests due to financial, travel or temperament-based limitations. In turn, this means that a population of dogs may not be prescribed therapy that has the potential to improve their lives. To best apply our knowledge of treating asymptomatic MVD, it is therefore necessary to explore alternative techniques that could be used to identify patients more likely to have advanced disease.

The HAMLET study aims to address this objective by evaluating whether levels of serum cardiac biomarkers, interpreted alongside a patient’s clinical information, can determine which dogs are likely to have cardiac enlargement and therefore would benefit from further investigation or treatment. The study is a prospective, multicentre, cross-sectional study led by primary investigators at the RVC. Data required for the HAMLET study are recorded from the standard clinical procedures used to evaluate asymptomatic MVD and submitted by participating veterinary cardiologists in the UK and Germany.

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

Impact      

The EPIC study found pimobendan extended the asymptomatic period of dogs with MVD by an average of 15 months. Dogs that received the drug also lived significantly longer than those receiving a placebo. Dogs receiving pimobendan benefited from a reduction of the risk of CHF or cardiac death by more than one third. After an interim analysis, the EPIC 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.

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