What is the EPIC Study?
The EPIC Study was the largest clinical study ever to be conducted amongst dogs with myxomatous mitral valve disease (MMVD). EPIC stands for Evaluating Pimobendan In Cardiomegaly and was an international, multi‑centre clinical study to determine whether chronic oral administration of pimobendan in dogs with evidence of increased heart size can delay the onset of clinical signs of congestive heart failure (CHF).1
What was the objective of the study?
To determine whether chronic oral administration of pimobendan in dogs with evidence of increased heart size secondary to preclinical myxomatous mitral valve disease (MMVD) can delay the onset of clinical signs of congestive heart failure (CHF).1
Why was this study so important?
There is currently no treatment licensed for the management of preclinical myxomatous mitral valve disease (MMVD). Nevertheless, there is a high level of interest among veterinarians in the treatment of preclinical MMVD.
The QUEST Study established pimobendan as the new standard of treatment for dogs with congestive heart failure (CHF) caused by MMVD as it extended survival time.2 The veterinary community also sought to answer this question: Can pimobendan also delay the onset of clinical signs of CHF?
Pimobendan has been efficacious in reducing mortality, as well as morbidity associated with CHF caused by MMVD. Pimobendan is proven to decrease preload and afterload, and this, in combination with pimobendan’s inotropic properties, may result in a reduction in cardiac size and filling pressures in dogs with significant cardiac remodelling secondary to MMVD. These effects are considered to be beneficial and, therefore, in dogs with preclinical MMVD, it was anticipated that pimobendan would delay the onset of pulmonary oedema and clinical signs.
Why was the ACVIM classification system used?
The ACVIM classification system is the newest, most up-to-date system developed and published by an international board of expert veterinary cardiologists.3
Who developed the study protocol?
The study protocol was developed by the independent group of lead investigators.
What was the study design?
The EPIC Study was a randomised, positive‑controlled, multi‑centre study conducted at 36 sites across Australia, North America, Asia, and Europe.
Patients were recruited over a 2‑year period and randomly allocated to either a pimobendan or a placebo treatment group, each group consisting of 180 dogs.
The clinical phase was designed to span 3 years and follow dogs to the primary endpoint (onset of clinical signs caused by left‑sided congestive heart failure or cardiac‑related death).
How many dogs were in the study? Why was this number chosen?
According to the following assumptions, 150 animals per group was sufficient to detect a difference in median time to onset of left‑sided congestive heart failure (CHF) with a power of 80%.
The length of the recruitment period was 2 years, and the maximum length of follow‑up was 5 years. A minimum of 3 years of follow‑up was granted following the accrual period.
Results of prior studies have shown that the median time to onset of left‑sided CHF in dogs with stage B2 chronic myxomatous mitral valve disease (MMVD) is around 27 months.
The study involved 2 treatment groups of 180 dogs each, for a total of 360 dogs. This allowed for those animals that did not reach the primary endpoint.
Where did the dogs come from?
The study involved 36 study centres in 11 countries across 4 continents. The countries included Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States.
Were the dogs given an ACE inhibitor?
No. According to the ACVIM Consensus Statement, there is no treatment recommendation for dogs in this stage of heart disease.3
What were the inclusion criteria?
Systolic heart murmur with maximal intensity over the mitral valve area
Echocardiographic evidence of myxomatous mitral valve disease (MMVD) defined as characteristic valvular lesions of the mitral valve apparatus
Presence of mitral regurgitation on the colour Doppler echocardiogram
Echocardiographic evidence of left atrial dilation
Radiographic evidence of cardiomegaly
Animals had to be at least 6 years of age
Animals had to have a body weight of 4.1–15 kg (9–33.1 lbs)
Why was there a weight limit for dogs participating in the study?
To ensure a homogenous group of dogs and because myxomatous mitral valve disease (MMVD) most commonly affects dogs within this weight range (4.1–15 kg, or 9–33.1 lbs)
How many investigators were involved?
There were 36 specialised veterinary cardiologists from around the globe participating in the EPIC Study.
How were the investigators chosen?
Each of the final 36 investigators was chosen by the lead investigative committee. All investigators were specialised veterinary cardiologists.
Where were the investigators located?
The study involved 36 study centres in 11 countries across 4 continents. The countries included Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, the United Kingdom, and the United States.
Who was the sponsor of the study?
How did the sponsor ensure that the results were independent?
Although Boehringer Ingelheim sponsored the study, the results—and the publication of those results—were controlled by the independent investigative committee. Both the lead investigative committee and the project statistician worked independently.
Study results were released after they were audited and evaluated by the lead investigators and independent statistician. In addition, the lead investigator was guaranteed the right to publish study results—regardless of the outcome.
When did the study begin and end?
The study began in 2010 and ran through to 2015.
The clinical phase followed a 2‑year recruitment period and spanned 3 years, following dogs to the primary endpoint (onset of clinical signs caused by left‑sided congestive heart failure or cardiac‑related death).
When were the results made available?
Findings of the EPIC Study were published in the November/December 2016 issue of the Journal of Veterinary Internal Medicine. Read the full study here.
What was the endpoint of the study?
The primary endpoint was a composite of the development of left‑sided congestive heart failure (CHF), cardiac‑related death, or euthanasia.
What were the results of the study?
The first EPIC Study publication showed that administration of pimobendan resulted in a 15‑month delay in time to primary endpoint compared with dogs receiving placebo. The composite primary endpoint was defined as the onset of left‑sided congestive heart failure (CHF), cardiac related death, or euthanasia. Dogs in the pimobendan group were significantly less likely to reach this endpoint. Median time to composite primary endpoint was 1228 days in the pimobendan group and 766 days in the placebo group (P=0.0038).1
In the EPIC Study, dogs in the pimobendan group experienced 60% more time in asymptomatic stage B2 of heart disease and 10% more life without CHF signs that impact quality of life (10% more life without CHF was calculated based on an estimated lifespan for all small‑ to medium‑sized dogs being 12.5 years. Fifteen months is equal to 1.25 years, which is 10% of 12.5 years).1
The second EPIC Study publication showed that treatment of preclinical myxomatous mitral valve disease (MMVD) (Stage B2) with pimobendan resulted in significantly reduced heart size in dogs with preclinical (Stage B2) MMVD. Heart size reduction was associated with increased time to the onset of CHF or cardiac-related death (CRD).4
What are the implications of the results of the study?
EPIC findings suggest that early treatment of preclinical MMVD delays onset of CHF in dogs. For veterinarians, this means they no longer have to adopt a ‘watch‑and‑wait’ approach to suspected preclinical cases of MMVD. This represents a significant shift in how veterinarians approach the diagnosis and management of MMVD.
What is the QUEST Study?
The QUEST Study was the largest clinical study ever conducted amongst dogs with congestive heart failure (CHF).
QUEST stands for Quality of Life and Extension of Survival Time, and was an international, multi-centre clinical study comparing
2 treatments used to combat CHF in dogs, pimobendan and an ACE inhibitor (benazepril hydrochloride).2
What is the QUEST Study design?
QUEST was a randomised, positive‑controlled, multi‑centre study conducted at 28 sites across Australia, Canada, and Europe.2
Patients were recruited over a 2‑year period and randomly allocated to either a pimobendan or benazepril hydrochloride treatment group, each group consisting of 130 dogs.2
The study spanned 3 years and followed dogs to death, euthanasia, or treatment failure leading to withdrawal from the study.2
How is the QUEST Study independent?
The protocol was developed by an independent committee.
The statistical analyses were conducted by an independent statistician.
The research paper was written by an independent publication committee and published in the Journal of Veterinary Internal Medicine.
The investigators were guaranteed the publishing rights of the study results regardless of the outcome.
What are the results of the QUEST Study?
The median survival for the whole population in the study was 188 days.2
The median survival for dogs receiving pimobendan was 267 days.2
The median survival for dogs receiving benazepril was 140 days.2
Survival was extended by 91% in dogs receiving pimobendan compared with those receiving benazepril hydrochloride.2*
What are the implications of the results of the QUEST Study?
The QUEST Study established pimobendan as the new standard of treatment for dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). The authors of the publication conclude: ‘This study offers the most compelling evidence to date demonstrating the beneficial effect of pimobendan when compared with benazepril for extending survival in dogs with CHF caused by MMVD when used in conjunction with other standard therapy.’2
What is the difference between the QUEST Study and the EPIC Study?
The EPIC Study differed from the QUEST Study in several significant ways:
It was larger in number of participants and countries;
Treatment timing was in the preclinical phase (no outward symptoms and Stage B2 heart disease) instead of clinical phase (patients exhibiting clinical signs and at Stage C heart disease); and
The onset of clinical signs of CHF, cardiac‑related death, or euthanasia—rather than death—were the primary variables under investigation
What is Boehringer Ingelheim?
Innovative medicines for people and animals have for more than 130 years been what the research-driven pharmaceutical company Boehringer Ingelheim stands for. Boehringer Ingelheim is one of the pharmaceutical industry’s top 20 companies and to this day remains family-owned. Day by day, some 50,000 employees create value through innovation for the three business areas human pharmaceuticals, animal health and biopharmaceutical contract manufacturing. In 2016, Boehringer Ingelheim achieved net sales of around 15.9 billion euros. With more than three billion euros, R&D expenditure corresponds to 19.6 per cent of net sales.
Social responsibility comes naturally to Boehringer Ingelheim. That is why the company is involved in social projects such as the “Making More Health” initiative. Boehringer Ingelheim also actively promotes workforce diversity and benefits from its employees’ different experiences and skills. Furthermore, the focus is on environmental protection and sustainability in everything the company does.
What is Boehringer Ingelheim Animal Health?
As the second largest animal health business in the world, Boehringer Ingelheim is committed to improving animal health. With more than 10,000 employees worldwide, Boehringer Ingelheim Animal Health has products available in more than 150 markets and a global presence in 99 countries. For more information about Boehringer Ingelheim Animal Health, click here.
What is the role of Boehringer Ingelheim in the EPIC Study?
Boehringer Ingelheim is the EPIC Study sponsor as well as the manufacturer of the first pimobendan product available to veterinarians.
Boehringer Ingelheim is committed to cardiology research and education and creating more ways to help treat canine heart disease.
What is pimobendan?
Pimobendan is an inodilator and is the first of a unique class of treatments for congestive heart failure (CHF) in dogs. It features
a complementary dual mode of action, with both vasodilatory and positive inotropic properties. As a balanced vasodilator, pimobendan dilates both veins and arteries resulting in a reduction in preload and afterload. As a positive inotrope, pimobendan acts directly on the heart, increasing cardiac output and tissue perfusion without increasing energy or oxygen consumption.4,5
Pimobendan is recommended for the treatment of CHF in dogs caused by dilated cardiomyopathy (DCM) or myxomatous mitral valve disease (MMVD).4
It is licensed for the treatment of the symptomatic stages of MMVD in all countries where the EPIC Study was conducted.
How does pimobendan work?
As an inodilator, pimobendan has a complementary dual mode of action:
Simultaneously dilates the blood vessels, both veins and arteries, around the heart and body
By dilating the blood vessels taking blood away from the heart, it decreases the work the heart must do to pump blood around the body and thereby reduces the afterload on the heart
By dilating the blood vessels that return blood to the heart, pimobendan reduces the pressure on the heart, thereby decreasing the preload on the heart
Strengthens the contractility of the heart muscle, thereby increasing cardiac output, without increasing energy or oxygen consumption.
What is an inodilator?
An inodilator (eg, pimobendan) is an agent that has both vasodilatory and positive inotropic properties in a single medication. Both modes of action work together to manage the clinical signs of congestive heart failure (CHF).4,5
What is meant by balanced vasodilator?
A balanced vasodilator simultaneously dilates veins and arteries and results in the reduction of both preload and afterload, easing the workload of the dog's failing heart.4
What is meant by positive inotrope?
A positive inotrope directly increases cardiac output. Some classes of positive inotropes achieve this increased output at the expense of an increase in energy consumption, causing the failing heart to work even harder.
Pimobendan achieves this without an increase in myocardial energy consumption. This is achieved by enhancing the Ca++ sensitization in the myocardium. The increase in cardiac output results in a direct increase in tissue perfusion.4,5
How is pimobendan different from other treatments?
Not only does pimobendan open the blood vessels, reducing resistance in the circulation and workload on the heart, it also differs from other commonly used heart medications by working directly on the heart to make it pump more efficiently without increasing energy expenditure.4,5
What are the benefits of treating with pimobendan?
There is no cure for congestive heart failure (CHF) in dogs, but previous clinical studies have shown that treatment with pimobendan improves the quality of the dog’s life quickly and also increases the survival time of dogs with CHF caused by myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM).3,5 The EPIC Study showed that administration of pimobendan resulted in a 15‑month delay in onset of clinical signs of CHF, cardiac‑related death, or euthanasia compared with dogs receiving placebo.
How does pimobendan impact the quality of life of the dog treated?
Various studies have shown a benefit in quality of life to dogs receiving pimobendan:
In the EPIC Study, dogs in the pimobendan group experienced 10% more life without congestive heart failure (CHF) signs that impact quality of life (10% more life without CHF was calculated based on an estimated lifespan for all small‑ to medium‑sized dogs being 12.5 years. Fifteen months is equal to 1.25 years, which is 10% of 12.5 years).
In the VetSCOPE Study, pimobendan rapidly improved the quality of life in dogs with CHF caused by myxomatous mitral valve disease (MMVD). The pimobendan‑treated dogs showed significantly greater improvements at day 56 in demeanour, exercise tolerance, and respiratory effort compared with dogs that were not treated with pimobendan.6
Pimobendan also significantly improves the quality of life in dogs with CHF caused by DCM. In a study of Doberman Pinschers, 80% of the dogs treated with pimobendan showed improvements in the quality‑of‑life measures (including exercise tolerance, coughing, dyspnea, and fatigue) compared with only 10% in the group not treated with pimobendan.7
In the PROTECT Study, the administration of pimobendan to Dobermans with preclinical DCM prolonged the time to the onset of clinical signs and extended survival.
How fast does pimobendan work?
Pet owners should begin to see an improvement in their dog typically within 1 week of starting treatment.
It is also possible that the initial improvement witnessed after 1 week may be followed by further improvements in coming weeks.
How does pimobendan impact the length of a dog’s life?
The EPIC Study showed that administration of pimobendan resulted in a 15‑month delay in onset of clinical signs of CHF, cardiac‑related death, or euthanasia compared with dogs receiving placebo.
In the QUEST Study, pimobendan significantly increased the survival time of dogs with congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). Dogs treated with pimobendan lived almost twice as long as dogs treated with an ACE inhibitor (267 days vs 140 days).2
Pimobendan has also been shown to increase the survival time of dogs with CHF caused by dilated cardiomyopathy (DCM). In a study completed in the UK, Doberman Pinschers treated with pimobendan lived 6 times longer than those treated with an ACE inhibitor (329 days vs 50 days).7
How is pimobendan administered?
Pimobendan is given orally to dogs twice daily at a total daily dose of 0.5 mg/kg. Pimobendan may be given alone or alongside other cardiac medications.
Is it safe to administer pimobendan to asymptomatic dogs?
Study results presented at ACVIM showed the effectiveness and safety of pimobendan when administered in the preclinical stage of other forms canine cardiac disease. These encouraging results led us to believe that pimobendan could be effective in preclinical mitral valve disease and that the investigation of this through the EPIC Study was useful and worthwhile.
Dogs in the EPIC Study benefited from free regular re‑evaluation by experts, meaning they were likely to receive a superior standard of care irrespective of whether they received the active drug or placebo. Additionally, safety reviews and interim analyses were planned as part of the EPIC Study, specifically, to monitor the safety of the study.
Why are clinical studies important to veterinary medicine?
Clinical studies are a key research tool for advancing medical knowledge and patient care.
Investigators participating in the EPIC Study researched whether pimobendan was effective in the preclinical stages of mitral valve disease. Other clinical studies conducted to evaluate the effects of pimobendan have shown positive results, which have subsequently led to the appropriate treatment of dogs worldwide. These results gave our team hope that the research of pimobendan in preclinical stages of mitral valve disease was worthwhile in studying.
Myxomatous mitral valve disease (mmvd) & congestive heart failure (chf)
What is myxomatous mitral valve disease (MMVD)?
As the name suggests, MMVD affects the mitral valve, which is located on the left side of the heart between the atrium and the ventricle.
MMVD is a slowly progressive condition in which the mitral valve thickens. Normally, heart valves form a perfect seal when closed, ensuring that blood flows in the right direction through the heart. Therefore, the function of the mitral valve is to channel blood from the left atrium into the left ventricle. However, in MMVD the thickening of the mitral valve results in an imperfect seal and allows blood to ‘leak’ backward into the atrium as the ventricle contracts.
How prevalent is myxomatous mitral valve disease (MMVD)?
MMVD affects about:8
10% of dogs between the ages of 5 and 8 years
20–25% of dogs between the ages of 9 and 12 years
30–35% of dogs more than 13 years of age
This form of heart disease usually occurs in small‑ to medium‑sized dogs. The most susceptible breeds are Cavalier King Charles spaniels, poodles, schnauzers, chihuahuas, and fox terriers. Also, male dogs are more commonly affected than females.
What are the stages of heart disease?
The American College of Veterinary Internal Medicine recognises 4 stages of heart disease and failure in dogs:3
Stage A: Dogs at high risk for heart disease but no disease is present
Stage B: A heart murmur is heard but there are no visible signs of heart failure
Stage B1: The heart does not appear enlarged or changed on an x‑ray
Stage B2: The heart does appear enlarged or changed on an x‑ray
Stage C: Evidence of heart failure is visible and treatment is necessary
Stage D: Characterised by heart failure that is getting hard to manage and is not responding to standard treatment
What occurs during congestive heart failure (CHF)?
As heart disease progresses, the heart weakens and blood continues to leak backward into the atrium. This overloads the atrium and causes fluid to leak out of the blood vessels into the lungs (known as pulmonary oedema). In addition, blood flow out of the heart slows, thus reducing blood flow to the key organs. At this stage, the signs of CHF become evident.
What are the clinical signs of congestive heart failure (CHF)?
The most common signs of CHF include:
Changes in breathing
- Difficulty breathing
- Shortness of breath
- Laboured breathing
- Rapid/fast breathing
Changes in behaviour
- Tiring easily
- Reluctance to exercise/not wanting to go for walks
- Less playful
- Slowing down/lack of energy
- Poor appetite
- Weight loss
- Restlessness, especially at night
Some or all of the clinical signs above may appear and can have an impact on the dog’s quality of life.
How is preclinical myxomatous mitral valve disease (MMVD) diagnosed?
If a veterinarian auscults a loud murmur during a physical examination, thoracic radiography and echocardiography can help in diagnosing preclinical MMVD.
How are the clinical stages of myxomatous mitral valve disease (MMVD) diagnosed?
The diagnosis of CHF caused by MMVD is usually preceded by the detection of a heart murmur during routine veterinary check‑ups using a stethoscope. A heart murmur is the sound caused by blood leaking backward into the atrium from the ventricle.
To diagnose CHF the veterinarian will need to complete a thorough clinical history and physical examination.
They may also recommend some of the following tests to aid in diagnosis:
Radiographs (X‑rays): to check for any enlargement of the heart or fluid accumulation in the lungs
Echocardiography (ultrasound): to show any thickening of the heart valve edges or enlargement of the chambers of the heart
How is heart failure caused by myxomatous mitral valve disease (MMVD) managed?
Treatment of CHF caused by MMVD begins when the dog shows clear clinical signs of heart failure and is tailored for the individual dog. Since surgery to prevent further deterioration is rarely possible in canine patients, management of heart failure seeks to improve quality of life and extend life expectancy through daily medication.
Is there a cure for heart disease in dogs?
Currently, there is no cure for heart disease in dogs caused by myxomatous mitral valve disease (MMVD), but treatments are available to help dogs live a longer life and feel better.
The success of any treatment, however, depends on various factors, including early detection and diagnosis.