What have we learned from the Veterinary Clinical Heart Failure Treatment Trials with Pimobendan?

The Edinburgh Trials
The Fuentes Study
The Smith Study
The European Trial
The PITCH Trial
The University of Guelph Trials
The DCM Trial
The CMVI Trial
The Fuentes Study: Fuentes et al: JVIM 2002: 255-261
Objective: To show that pimobendan will increase survival and quality of life for dogs with DCM when added to conventional therapy consisting of diuretics, ACE inhibitors, and digoxin
Study Design:
Two populations of dogs were studied: Doberman Pinschers with DCM and Cocker Spaniels with DCM and CHF
Each group was randomized separately into dogs to receive pimobendan or placebo in addition to conventional therapy consisting of furosemide, enalapril, and digoxin
This was a prospective, randomized, placebo controlled, double blinded trial
10 Doberman Pinschers (5 receiving enalapril, and 5 receiving placebo) were enrolled
10 Cocker Spaniels (5 receiving enalapril, and 5 receiving placebo) were enrolled
Results:
The Doberman Pinschers:
Average time to death:
Pimobendan dogs: 329 days
Placebo dogs: 50 days
Difference between treatment groups: P < 0.02
There was a significant improvement in NYHA Class score with the addition of pimobendan
The Cocker Spaniels:
Average time to death:
Pimobendan dogs: 1037 days
Placebo dogs: 537 days
Difference between treatment groups: P = 0.77
There was a significant improvement in NYHA Class score with the addition of pimobendan
Limitations:
Doberman Pinschers:
3 of the pimobendan Dobermans had atrial fibrillation at the time of enrolment
1 of the placebo Dobermans had atrial fibrillation at the time of enrolment
Atrial fibrillation carries a profound negative impact on survival hence significantly disadvantaging the placebo group
The Cocker Spaniels:
9 of the Cocker Spaniels failed to reach the endpoint of cardiac death (6 dogs were still alive at the end of the study and 3 dogs died of non-cardiac causes)
Thus the study was not designed to find a difference between the Cocker Spaniel treatment groups
Our Conclusions:
Although the study has a strong bias in favour of pimobendan due to the higher prevalence of atrial fibrillation in the non-pimobendan group, the duration of survival in the pimobendan dogs is so much greater than we historically observe in our non-pimobendan dogs that we feel there must have been a favourable impact of pimobendan.
Although it is profoundly difficult to assign NYHA Class scores in dogs with heart failure (this classification scheme is much better suited to people than dogs – it really doesn’t work in dogs), this data suggests an improvement in quality of life based on NYHA Class score reduction with pimobendan.
This study sheds no light on the role of pimobendan in Cocker Spaniels with DCM and CHF.

The Smith Study: Smith et al: abstract JVIM 2003
Objective: To show that pimobendan will increase survival and quality of life as compared with an ACE inhibitor for dogs with CMVI when added to conventional therapy consisting of diuretics
Study Design:
A 6 month prospective, randomized, single blinded trial comparing the effect of pimobendan vs ramipril in dogs with CHF due to CMVI
44 dogs were enrolled
Endpoints:
Death due to heart failure
Euthanasia due to heart failure
Discontinued from the study
Number of hospital revisits
Results:
15 pimobenadan dogs and 9 ramipril dogs reached the 6 month time point
O pimobendan dogs and 4 ramipril dogs died of HF
4 of each group were euthanized for HF
O pimobedan dogs and 2 ramipril dogs were discontinued due to HF
3 pimobendan dogs and 2 ramipril dogs were euthanized for non-cardiac etiologies
# of adverse HF events:
Pimobendan dogs = 4
Ramipril dogs = 10
5x’s increase risk of adverse outcome in the ramipril group (death, euthanasia, withdrawal) (P = 0.036)
3x’s increase risk of repeated hospital visits in the ramipril group (P = 0.115)
Limitations:
Single blinded study
The withdrawal/discontinuation from the study is a weak criteria for an endpoint
Our Conclusions:
This study represents the strongest evidence in favour of pimobendan use in canine CMVI.
Number of adverse outcomes is used as a surrogate for survival. Clearly number of outcomes is not survival.
The criteria of discontinuation from the study is an unfortunate criteria that carries a profound degree of inherent subjectivity.

The PITCH Trial: Lombard et al: BSAVA Congress 2000
Objective:To show that pimobendan will increase survival and quality of life for dogs with CHF due to DCM and CMVI when added to conventional therapy consisting of diuretics, and digoxin when compared with ACE inhibitor therapy
Study Design:
A prospective randomized trial with 2 phases:
A 4-week quality of life study
An optimal survival study
The dogs were randomized into three treatment groups
A pimobendan group
DCM dogs: 32 dogs
CMVI dogs: 4 dogs
A pimobendan plus benazepril group
DCM dogs: 25 dogs
CMVI dogs: 9 dogs
A benazepril group:
DCM dogs: 24 dogs
CMVI dogs: 11 dogs
Endpoints:
Died, dropped out, euthanized for heart failure
Results:
Overall improvement in both pimobendan treatment groups compared to the benazepril alone group
73 dogs on pimobendan in the long term study
16 dogs were alive at the end of the trial
37 dogs on benazepril in the long term study
5 dogs were alive at the end of the trial
Average survival time:
Pimobendan dogs: 232 days
Benazepril dogs: 164 days
Median survival time:
Pimobendan dogs: 217days
Benazepril dogs: 42 days
Difference between treatment groups: P = 0.02
Limitations:
There is some question that the optional survival study was not completely blinded
One of the CMVI dogs had tricuspid valve insufficiency as the main problem
Too few dogs were enrolled into the CMVI group and too few into the pimobendan alone treatment limb of the CMVI group
There is no separation of dogs into CMVI vs DCM so we cannot determine the utility of pimobendan in one cause of heart failure versus the other cause of heart failure
Our Conclusions: This study does not address the role of pimobendan to increase survival or quality of life in the separate groups of DCM and CMVI. As the DCM group is considerably larger than the CMVI group one might wonder whether the improved survival and quality of life is entirely due to benefit in the DCM dogs alone. So does pimobendan increase survival or quality of life in the CMVI dogs? The Smith study suggests an improvement in survival. It however is not a survival study. Furthermore, the Smith study did not demonstrate improved quality of life.

University of Guelph Trials:
DCM Study: O’Grady and Minors et al: Abstract ACVIM 2003
Objectives: To show that pimobendan is superior to placebo to increase survival and quality of life for dogs with DCM when added to conventional therapy consisting of diuretics and ACE inhibitors
Study Design:
Prospective, single blinded, randomized trial involving Doberman Pinschers with CHF due to DCM
16 Dobermans were to receive pimobendan or placebo: 8 received pimobendan; 8 received placebo
Excluded dogs with atrial fibrillation
Endpoints:
Treatment failure - defined as a failure of 5 mg/kg TID of furosemide to control respiratory distress or death due to cardiac reasons prior to this dose of furosemide
Death
Dogs that met the treatment failure criteria of a failure of 5 mg/kg TID of furosemide to control respiratory distress were offered both therapies (placebo and pimobendan)

Results:
Quality of life assessment: Body weight, diuretic dose, attitude score, respiratory function score, stamina score, and total cumulative score were significantly improved in the pimobendan group compared to the placebo group
Average time to treatment failure: dogs were censored for failure to meet the treatment failure criteria
Pimobendan dogs (7 dogs): 131 days
Placebo dogs (8 dogs): 26 days
P = 0.002
Average time to death: dogs were censored for failure to meet the cardiac death criteria (intention to treat analysis used)
Pimobendan dogs (6 dogs): 146 days
Placebo dogs (8 dogs): 79 days
P = 0.04
Limitations:
Only single blinding (only owner was blinded)
Small numbers
Dobermans only
Our Conclusions: This is the first study to definitively demonstrate the benefit of pimobendan on both quality of life and survival in DCM dogs

CMVI Study: O’Grady and Minors et al: Abstract JVIM 2003
Objectives: To show that pimobendan is superior to benazepril to increase survival and quality of life for dogs with CMVI when added to conventional therapy consisting of diuretics.
Study Design:
Prospective, double blinded, randomized trial involving small-breed dogs with CHF due to CMVI
15 dogs were randomized to pimobendan or benazepril: 8 received pimobendan; 7 received benazepril
Excluded Cocker Spaniels, dogs >25 kg, dogs with atrial fibrillation, dogs with significant concurrent systemic disease
Endpoints:
Treatment failure - defined as a failure of 5 mg/kg TID of furosemide to control respiratory distress or death due to cardiac reasons prior to this dose of furosemide
Death
Dogs that met the treatment failure criteria of a failure of 5 mg/kg TID of furosemide to control respiratory distress were offered both therapies (benazepril and pimobendan).
Results:
Quality of life assessment: No significant difference between groups
Average time to treatment failure:
Only 4 dogs in each group reached treatment failure, and dogs were censored for failure to meet the treatment failure criteria
Trend for pimobendan group to have longer time to treatment failure, however difference not statistically significant
Average time to death: dogs were censored for failure to meet the cardiac death criteria (intention to treat analysis used)
Pimobendan dogs (5 dogs): 230 days
Placebo dogs (3 dogs): 198 days
P = 0.77
Limitations:
Very few dogs have reached the endpoints
Data analysis based on only 15 dogs out of a desired 40 to be enrolled (small numbers thus far)
Our Conclusions: This is a study in progress. Too few dogs have been enrolled and too few dogs have reached the endpoints to make any conclusions.

Алексей Бокарёв
14.2.2007, 12:26
Прикладываю также собственный перевод инструкции к ветмедину:

ИНСТРУКЦИЯ ПО ПРИМЕНЕНИЮ

Лекарственное средство, действующее на сердечно-сосудистую систему
Vetmedin® 1,25 mg {также есть дозировки 2,5 и 5 мг}
---www.vetphoto.ru---

Действующее вещество: Пимобендан
Для животных: Собаки

Состав
1 капсула препарата Vetmedin® 1,25 мг содержит: действующего вещества Пимобендана 1,25 мг

Форма выпуска и содержание
Упаковка, содержащая 100 капсул.

Фирма-производитель
Boehringer Ingelheim Vetmedica GmbH Binger Str. 173 55216 Ingelheim

Область применения
Лечение сердечной недостаточности у собак, вызванной дилатационной кардиомиопатией или недостаточностью клапанов (регургитация митрального и/или трикуспидального клапанов) с характерными симптомами, такими как, например, кашель, одышка, снижение толерантности к нагрузкам или асцит.

Противопоказания
Vetmedin® не следует применять при гипертрофической кардиомиопатии и заболеваниях, при которых увеличение сердечного выброса не может быть достигнуто по функциональным или анатомическим причинам (например, при стенозе устья аорты).
Поскольку Vetmedin® выделяется из организма преимущественно через печень, этот препарат не должен применяться у собак с тяжелыми формами печеночной недостаточности.

Меры предосторожности
У собак больных сахарным диабетом во время лечения необходимо осуществлять регулярный контроль уровня глюкозы в крови.
Взаимодействие с другими средствами
В фармакологических исследованиях не удалось установить никакого взаимодействия между сердечным гликозидом строфантином и пимобенданом. Индуцированный пимобенданом подъем фракции сократимости ослабляется антагонистами кальция, такими как верапамил и бета-адреноблокаторами, такими как пропранолол.

Дозировка, форма и сроки применения
Дозировка составляет 0,5 мг действующего вещества на 1 кг массы тела, суточную дозу распределяют на 2 приема. Это соответствует 1 капсуле Vetmedin® 1,25 мг утром и 1 капсуле Vetmedin® 1,25 мг вечером на 5 кг живой массы. Широта терапевтической дозировки колеблется от 0,2 мг до 0,6 мг на 1 кг массы тела, разделенные на 2 приема в сутки, ежедневно.
Vetmedin® необходимо давать через рот. Дача препарата Vetmedin® должна происходить примерно за один час до кормления. Vetmedin® может назначаться также в комбинации с мочегонным средством, например, фуросемидом.
В случае декомпенсированной сердечной недостаточности рекомендована пожизненная продолжительная терапия препаратом Vetmedin®. Поддерживающая доза должна быть подобрана индивидуально в зависимости от тяжести заболевания.

Рекомендации в случае передозировки
В случае передозировки производят симптоматичное лечение.

Побочные действия
В редких случаях встречается легкое положительно хронотропное действие (повышение ЧСС), а также рвота. Эти эффекты зависят от дозы и могут быть предотвращены сокращением дозы. Если Вы отмечаете побочные явления у Вашего животного, которые не представлены в этой инструкции, сообщите ее {их} Вашему ветеринарному врачу или сотруднику аптеки.

Время выведения
Не указано.
Примечание: у продуктивных животных не применяют

Примечания и указания по хранению лекарственного средства
По истечению срока указанного на флаконе и на внешней упаковке лекарственное средство не применяют.
Лекарство по истечении на контейнере и внешней упаковке указанного срока годности больше не применяют.
Хранить при температуре не выше 25 °C.

Меры предосторожности при утилизации не использованных лекарственных средств или прочие меры предосторожности для сохранения безопасности окружающей среды.
Неизрасходованные ветеринарные препараты необходимо передавать в специализированные места сбора вредных веществ. При общей утилизации отходов с домашним мусором необходимо обеспечивать такие условия, при которых исключается возможность нецелевого использования этих отходов. Ветеринарные препараты нельзя утилизировать по средствам канализации со сточными водами.

Дата формулировки инструкции: 16.05.2001