Pimobendan: A Treatment for Preclinical Heart Failure

KE Joubert BVSc, MMedVet (Anaes) – Extraordinary Lecturer: Pharmacology – Department of Paraclinical Sciences, Faculty of Veterinary Science,

University of Pretoria,

Reviewed: Marlies Bohm BVSc DSAM MMedVet(Med) DipECVIM -CA

dog-on-rock

Heart disease is one of the top 5 causes of death in dogs, in the United Kingdom with 75% of these cases being from mitral valve disease (MVD).

Heart disease is one of the top 5 causes of death in dogs, in the United Kingdom with 75% of these cases being from mitral valve disease (MVD). Heart failure secondary to MVD is classified according to the 2009 American College of Veterinary Internal Medicine (ACVIM) consensus statement. Stage A patients are at risk of heart disease according to their age and breed disposition with no clinical signs or evidence of heart disease. Stage B heart failure is divided into two stages. Stage B1 are asymptomatic patients without radiographic or echocardiographic evidence of compensation (i.e. heart murmur only) and stage B2 are asymptomatic patients with radiographic or echocardiographic evidence of compensation. Stage C patients have clinical heart disease with radiographic and echocardiographic evidence and require treatment to control the disease. Stage D patients are in refractory or end stage heart disease.

The QUEST (Quality of Life and Extension of Survival Time) study (2008) showed that dogs, in Stage C, treated with pimobendan, in conjuction with other standard treatment, for congestive heart failure (CHF), secondary to MVD, reached the primary end point in 267 days versus those treated with benazepril and other standard therapy, which took 140 days. The primary end points were sudden cardiac death, euthanasia due to cardiac disease or treatment failure leading to withdrawal from trial. To be included into the study dogs were required to be more than 5 years of age, weigh between 5 and 20kg, have a heart murmur of moderate to high intensity, have echocardiographic evidence of mitral valve disease and cardiac enlargement, radiographic evidence of pulmonary oedema and cardiac enlargement and clinical signs of suggestive of cardiac failure.

The second part of the QUEST study was published in 2013 and evaluated the quality of life (QOL) in patients receiving either pimobendan or benazepril. Good QOL in these patients was defined as alleviation of the clinical signs caused by CHF with resumption or near resumption of normal daily activities. Patients receiving pimobendan required 98 days before treatment was intensified compared to 59 days in the benazepril group. The QOL of life was similar between the two groups. Pimobendan maintained QOL of life for a longer duration of time, compared to benazepril. The overall conclusion from the two QUEST studies is that treatment with pimobendan maintained a good QOL for longer and increased the survival time by 127 days compared to benazepril.

The reality of treating patients with heart disease is that combination therapy is often required. In clinical practice, pimobendan and benazepril are often used together with other medications such as furosemide, beta blockers, spironolactone, calcium channel blockers, etc. These medications are often adjusted according to the clinical condition of the patient and require frequent follow up visits.

One the dilemmas in the medical management of cardiac disease has been when to start treating:

• when patient has evidence of a heart disease such as a murmur (Stage B)?

• when patient is showing adaptive changes due to the heart disease (Stage B2)?

• or only when the patient is showing clinical signs due to heart disease (Stage C)?

Evaluation of the preclinical use of pimobendan started with dilated cardiomyopathy (DCM) in Doberman Pinschers. This study was known as the PROTECT (Pimobendan Randomized Occult DCM Trial to Evaluate Clinical signs and Time to heart failure) study. The PROTECT study enrolled Doberman Pinschers between the ages of 4 and 9 years of age that had preclinical echocardiographic evidence of DCM but no clinical signs related to DCM. The primary end point of the study was established as the onset of CHF or sudden death from heart disease. Dogs receiving pimobendan took 718 days to achieve the primary end point while dogs in the placebo group which took 441 days.

A secondary end point of time from onset of clinical signs to death from cardiac disease was also evaluated as part of an unblinded study. Dogs receiving pimobendan survived for a median of 623 days compared to placebo group at 466 days. Similar results have been shown in Irish wolfhounds where median time to primary endpoint, onset of CHF or sudden death, was significantly longer for pimobendan (1,991 days) compared to methyldigoxin (1,263 days) or benazepril HCl (997 days) treated dogs.

The PROTECT study showed that pimobendan treatment of Doberman Pinschers with preclinical disease (Stage B2) DCM was beneficial due to the delay in the onset of the clinical signs of CHF. Thus pimobendan became the first recognised treatment in pre-clinical DCM in 2012

Research into the use of pimobendan in the preclinical phase of mitral valve disease started in October 2010 and is known as the EPIC (Evaluation of Pimobendan in Cardiomegaly) study. The EPIC study was conducted across 4 continents, 11 countries and 36 trial centres. The EPIC study included 360 dogs and took 5 years to complete.

For dogs to be included in the EPIC study they had to be in Stage B2 Heart disease and also fulfil the following specific criteria:

a. Be 6 years or older,

b. Weigh between 4.1 and 15 kg,

c. Have a systolic heart murmur of Gr 3/6 or louder

d. Have echocardiographic evidence of mitral valve disease: left atrial-to-aortic ratio ≥1.6, normalized left ventricular internal diameter in diastole ≥1.7 and vertebral heart sum (VHS)>10.

Dogs were treated with either pimobendan or a placebo. The primary end-point was the development of left sided congestive heart failure, euthanasia due to heart disease or death due to cardiac disease. Left sided heart failure was considered present when radiographic evidence of cardiogenic pulmonary oedema (interstitial or alveolar lung pattern) and clinical signs of heart failure (increased respiratory effort, increase respiratory rate) were present.

The median time taken for dogs to reach the primary end point in the pimobendan group was 1228 days (3.4 years) compared to 766 days (2.1 years) in the placebo group. The difference between the two groups is 462 days or 15 months. The administration of pimobendan to dogs that met the clinical, radiographic and echocardiographic inclusion criteria, resulted in a significant prolongation of the preclinical period.

In summary using pimobendan in MVD in dogs that meet the inclusion criteria described above, will delay the onset of clinical disease by a median 462 days. With good clinical management, the QUEST study showed us that the use of pimobendan with clinical heart failure can increase survival time with good quality of life by 127 days compared to benazepril therapy. Pimobendan may add more quality days to the lives of canine patients with mitral valve disease if started in Stage B2 heart failure and continued through into Stage C heart failure.

***For dogs to be included in the EPIC study they had to be in Stage B2 heart disease and also fulfil the following specific criteria:

• Be 6 years or older,

• Weigh between 4.1 and 15 kg,

• Have a systolic heart murmur of Gr 3/6 or louder

• Have echocardiographic evidence of mitral valve disease,

• left atrial-to-aortic ratio ≥1.6,

• normalised left ventricular internal diameter in diastole ≥1.7,

• vertebral heart score (VHS) >10.

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