This site provides information on the EPIC study and details on case recruitment for veterinary professionals worldwide. Pimobendan is a prescription only medicine, licensed for the treatment of congestive heart failure due to mitral valve disease or dilated cardiomyopathy.

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Evaluating Pimobendan in Cardiomegaly
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FAQs

You will find answers to most of your questions below. But if you don’t, please contact info@epictrial.com, and we will respond quickly.

EPIC

What is EPIC?
What is the objective of the study?
Why is this study so important?
Why is the ACVIM classification system being used?
Who developed the study protocol?
What is the study design?
How many dogs are in the study? Why was this number chosen?
Where will the dogs come from?
Will dogs be given an ACE inhibitor?
What are the inclusion criteria?
Why is there a weight limit for dogs participating in the study?
How many investigators are involved?
How were the investigators chosen?
Where are the investigators located?
Who is the sponsor of EPIC?
How will the sponsor ensure that the results are independent?
When will the study begin and end?
When will results be available?
Will the results be published regardless of outcome?
What is the endpoint of the study?

 

QUEST

What is the QUEST trial?
What is the QUEST trial design?
How is the QUEST trial independent?
What are the results of the QUEST trial?
What are the implications of the results of the QUEST trial?
What is the difference between QUEST and EPIC?

 

BIVI

What is Boehringer Ingelheim?
What is Boehringer Ingelheim’s role in the EPIC trial?

 

PIMOBENDAN

What is pimobendan?
How does pimobendan work?
What is an inodilator?
What is meant by balanced vasodilator?
What is meant by positive inotrope?
How is pimobendan different from other treatments?
What are the benefits of treating with pimobendan?
How does pimobendan impact the quality of life of life of the dog treated?
How fast does pimobendan work?
How does pimobendan impact length of dog’s life?
How is pimobendan administered?
When should treatment with pimobendan begin?
Is it safe to administer pimobendan to asymptomatic dogs?
Why are clinical trials important to veterinary medicine?

 

Myxomatous Mitral Valve Disease (MMVD) & Congestive Heart Failure (CHF)

What is Myxomatous Mitral Valve Disease (MMVD)? How prevalent is Myxomatous Mitral Valve Disease (MMVD)?
How prevalent is Myxomatous Mitral Valve Disease (MMVD)?
What is Congestive Heart Failure (CHF)?
What are the clinical signs of Congestive Heart Failure (CHF)?
How are Myxomatous Mitral Valve Disease (MMVD) and Congestive Heart Failure (CHF) diagnosed?
Is there a cure for Congestive Heart Failure (CHF) in dogs?
How are Myxomatous Mitral Valve Disease (MMVD) and Congestive Heart Failure (CHF) managed?

 

EPIC

What is EPIC?

The EPIC trial is the largest clinical study ever to be conducted amongst dogs with myxomatous mitral valve disease (MMVD). EPIC stands for Evaluating Pimobendan In Cardiomegaly, and is 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).

What is 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 signs of congestive heart failure (CHF).

Why is 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) due to MMVD. Now the veterinary community is seeking the answer to the question – Can pimobendan also delay the onset of clinical signs of CHF?1
  • 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, could be anticipated to delay the onset of pulmonary oedema and clinical signs.
Why is the ACVIM classification system being used?

The ACVIM classification system is the newest, most up-to-date system developed and published by an international board of expert veterinary cardiologists.2

Who developed the study protocol?

The study protocol was developed by the independent group of lead investigators.

What is the study design?
  • EPIC is a randomised, positive-controlled, multi-centre trial conducted at 36 sites across Australia, North America, Asia and Europe.
  • Patients will be recruited over a two-year period and randomly allocated to either a pimobendan or a placebo treatment group, each group will consist of 180 dogs.
  • The clinical phase will span three 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 are in the study? Why was this number chosen?
  • According to the following assumptions, 150 animals per group are 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 is two years and the maximum length of follow-up five years. A minimum of three years follow-up will be 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 involves two treatment groups of 180 each, for a total of 360 dogs. This will allow for those animals that do not reach the primary endpoint.
Where will the dogs come from?

The study involves 36 trial centres in 11 countries across four continents. The countries included are Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, United Kingdom and the United States.

Will dogs be given an ACE inhibitor?

No, in the recently published ACVIM Consensus Statement, there is no treatment recommendation for dogs in this stage of heart disease.2

What are 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 must be at least 6 years of age.
  • Animals must have a body weight of 4.1 – 15 kg (9 – 33.1 lbs).
Why is 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.

How many investigators are involved?

There are 36 specialized veterinary cardiologists participating in EPIC.

How were the investigators chosen?

Each of the final 36 investigators was chosen by the lead investigative committee. All investigators are specialized veterinary cardiologists.

Where are the investigators located?

The study involves 36 trial centres in 11 countries across four continents. The countries included are Australia, Canada, France, Germany, Italy, Japan, The Netherlands, Spain, Sweden, United Kingdom and the United States.

Who is the sponsor of EPIC?

Boehringer Ingelheim.

How will the sponsor ensure that the results are independent?
  • Although Boehringer Ingelheim is sponsoring the trial, the results – and the publication of those results – are controlled by the independent investigative committee.  Both the lead investigative committee with the project statistician are working independently.
  • Study results will not be released until after they are audited and evaluated by the lead investigators and independent statistician.  In addition, the lead investigator is guaranteed the right to publish study results – regardless of the outcome.
When will the study begin and end?
  • The study will begin in 2010 and run through to 2015.
  • The clinical phase follows a two-year recruitment period and will span three years, following dogs to the primary endpoint (onset of clinical signs caused by left-sided congestive heart failure or cardiac-related death).
When will results be available?

Upon completion of the trial, in approximately 2015, the manuscript will be drafted and submitted to a major veterinary journal and should appear shortly thereafter.

Will the results be published regardless of outcome?

Yes, the lead investigator, Professor Adrian Boswood, has the right to publish the results of EPIC study regardless of the outcome.

What is the endpoint of the study?

The primary endpoint is a composite of the development of left-sided congestive heart failure (CHF) or cardiac death.

QUEST

What is the QUEST trial?
  • The QUEST trial was the largest clinical study ever to be 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 trial comparing two treatments used to combat CHF in dogs, pimobendan and an ACE-inhibitor (benazepril hydrochloride).1
What was the QUEST trial design?
  • QUEST was a randomised, positive-controlled, multi-centre trial conducted at 28 sites across Australia, Canada and Europe.1
  • Patients were recruited over a two-year period and randomly allocated to either a pimobendan or benazepril hydrochloride treatment group, each group consisting of 130 dogs.1
  • The trial spanned three years and followed dogs to death, euthanasia or treatment failure leading to withdrawal from the trial.1
How is the QUEST trial 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 trial?
  • The median survival for the whole population in the study was 188 days.1
  • The median survival for dogs receiving pimobendan was 267 days.1
  • The median survival for dogs receiving benazepril was 140 days.1
  • Survival was extended by 91% in dogs receiving pimobendan compared with those receiving benazepril hydrochloride.1, §
What are the implications of the results of the QUEST trial?

The QUEST study established pimobendan as the new standard of treatment for dogs with congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD).

The authors of the publication conclude:
    “The study offers the most compelling evidence to date demonstrating the beneficial effect of 
    pimobendan when compared to benazepril for extending survival in dogs with CHF due to MMVD when used 
    in conjunction with other standard therapy.” 1

What is the difference between QUEST and EPIC?

EPIC differs from QUEST in several significant ways:
  • It is even larger in number of participants and countries;
  • Treatment timing is preclinical instead of clinical; and
  • The onset of congestive heart failure, rather than death, is the primary variable under investigation.

What is Boehringer Ingelheim?
  • The Boehringer Ingelheim group is one of the world's 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 138 affiliates in 47 countries and approximately 41,300 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.
  • In 2008, Boehringer Ingelheim posted net sales of US $17 billion (11.6 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.
What is Boehringer Ingelheim’s role in the EPIC trial?
  • Boehringer Ingelheim is the EPIC trial sponsor as well as being the manufacturer of pimobendan.
  • Boehringer Ingelheim is committed to cardiology research and education and creating more ways to help treat canine heart disease.

PIMOBENDAN

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.3,4,5
  • Pimobendan is recommended for the treatment of CHF in dogs due to 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 trial will be conducted.
How does pimobendan work?

As an inodilator pimobendan has a complementary dual mode of action: 

Vasodilator3,4
  • 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 has to 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.
Positive Inotrope3,4,5
  • Strengthens the contractility of the heart muscle thereby increasing cardiac output, without increasing energy or oxygen consumption.
What is an inodilator?

An inodilator, for example 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).3,4,5

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.3,4

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. 3,4,5
How is pimobendan different from other treatments?

Not only does pimobendan open up 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.3,4,5

What are the benefits of treating with pimobendan?

There is no cure for congestive heart failure (CHF) in dogs but 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 due to myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM).2,5

How does pimobendan impact the quality of life of the dog treated?
  • In the VetSCOPE study, pimobendan rapidly improved the quality of life in dogs with congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD). The pimobendan-treated dogs showed significantly greater improvements at day 56 for demeanour, exercise tolerance, and respiratory effort compared to those dogs that were not treated with pimobendan.6
  • Pimobendan also significantly improves the quality of life in dogs with CHF due to dilated cardiomyopathy (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, dyspnoea & fatigue) compared to only 10% in the group not treated with pimobendan.7
How fast does pimobendan work?
  • Pet owners should begin to see an improvement in their dog typically within one week of starting treatment.
  • It is also possible that the initial improvement witnessed after one week may be followed by further improvements in following weeks.
How does pimobendan impact the length of a dog’s life?
  • In the QUEST study, pimobendan significantly increased the survival time of dogs with congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD).  Dogs treated with pimobendan lived almost twice as long as the dogs treated with an ACE inhibitor (267 days versus 140 days).1
  • Pimobendan has also been shown to increase the survival time of dogs with CHF due to dilated cardiomyopathy (DCM).  In a study completed in the UK, Doberman Pinschers treated with pimobendan lived six times longer than those treated with an ACE inhibitor (329 days versus 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.

When should treatment with pimobendan begin?
  • Treatment with pimobendan should be initiated at the onset of the clinical signs of congestive heart failure (CHF) due to myxomatous mitral valve disease (MMVD) and dilated cardiomyopathy (DCM).
  • According to the recently published ACVIM Consensus Statement (Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease), treatment with pimobendan is recommended as standard of care for dogs in Stage C.  A dog is classified as a Stage C if it has a structural cardiac abnormality with current or previous clinical signs of heart failure.1
Is it safe to administer pimobendan to asymptomatic dogs?

Recent study results presented at ACVIM show the effectiveness and safety of pimobendan when administered in the preclinical stage of other forms canine cardiac disease. These encouraging results lead us to believe that pimobendan may be effective in pre-clinical mitral valve disease and that the investigation of this through the EPIC trial is useful and worthwhile.

Dogs in the EPIC study benefit from free regular re-evaluation by experts meaning they are likely to receive a superior standard of care irrespective of whether they receive the active drug or placebo. Additionally, Safety reviews and interim analyses are planned as part of the EPIC study; specifically to monitor the safety of the study.

Why are clinical trials important to veterinary medicine?

Clinical trials are a key research tool for advancing medical knowledge and patient care.

Investigators participating in the EPIC trial are researching whether or not pimobendan is effective in the pre-clinical stages of mitral valve disease. While our investigators do not yet know the outcome of the EPIC investigation, other clinical trials conducted to evaluate the effects of pimobendan have shown positive results which have subsequently led to the appropriate treatment of dogs worldwide. These results give our team hope that the research of pimobendan in pre-clinical stages of mitral valve disease is 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
This form of heart disease usually occurs in small-to medium-size 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 is 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:
  • Coughing
  • 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
    • Depressed/withdrawn
  • Poor appetite
  • Weight loss
  • Fainting/collapsing
  • Weakness
  • 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 are Myxomatous Mitral Valve Disease (MMVD) and Congestive Heart Failure (CHF) diagnosed?
  • The diagnosis of CHF due to 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:
  • 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
  • Blood tests 
Is there a cure for Congestive Heart Failure (CHF) in dogs?
  • Currently there is no cure for CHF 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.
How are Myxomatous Mitral Valve Disease (MMVD) and Congestive Heart Failure (CHF) managed?

Treatment of CHF due to 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.

References

1Häggström J, Boswood A, O'Grady M, et al. Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: The QUEST study. J Vet Intern Med 2008; 22:1124–1135.

2Atkins C et al. Guidelines for the Diagnosis and Treatment of Canine Chronic Valvular Heart Disease. J Vet Intern Med 2009; 23: 1142-1150.

3CVM Update, Food and Drug Administration Website. Available at: http://www.fda.gov/cvm/CVM_Updates/heartfailureUp.htm.

4Vetmedin (pimobendan) Chewable tablets [Package Insert]. St. Joseph, MO. Boehringer Ingelheim Vetmedica, Inc. 2007.

5Gordon SG, Miller MQ, Saunders AB. Pimobendan in heart failure-a silver bullet? J Am Anim Hosp Assoc 2006:42:90-93.

6Lombard CW, Jons O, Bussadori CM. Clinical efficacy of pimobendan versus benazepril for the treatment of acquired atrioventricular valvular disease in dogs. J Am Anim Hosp Assoc 2006; 42:249-261.

7Luis-Fuentes V et al. A double-blind, randomized, placebo-controlled study of pimobendan in dogs with dilated cardiomyopathy. J Vet Intern Med 2002; 16:255-261.

8Sisson D. Valvular heart disease in dogs. Abstract at WSAVA 2002.

§Survival was defined as the composite endpoint of cardiac death, euthanasia due to heart failure or treatment failure.

 

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Prof. Jens Häggström

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Prof. Adrian Boswood

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