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J Vet Intern Med 2002;16:255–261
A Double-Blind, Randomized, Placebo-Controlled Study of
Pimobendan in Dogs with Dilated Cardiomyopathy
Virginia Luis Fuentes, Brendan Corcoran, Anne French, Karsten E. Schober, Rainer Kleemann,
and Claus Justus
A double-blind, randomized, placebo-controlled study was conducted to examine the effect on heart failure class and survival of
pimobendan, an oral calcium-sensitizing inodilator, in dogs with dilated cardiomyopathy (DCM). Pimobendan (0.3–0.6 mg/kg body
weight/d) or placebo was administered to English Cocker Spaniels (CSs; n ⫽ 10) and Doberman Pinschers (DPs; n ⫽ 10) that
had DCM in addition to background therapy of furosemide, enalapril, and digoxin. Addition of pimobendan to standard triple
therapy was associated with a significant improvement in heart failure class, regardless of breed (P ⬍ .02, Mann-Whitney rank
sum test). Overall, 8 of 10 animals in the pimobendan-treated group, and 1 of 10 animals in the placebo group improved their
heart failure status by at least 1 modified New York Heart Association functional class after initial stabilization (P ⫽ .005, Fisher’s
exact test). Pimobendan had no significant effect on survival in the CSs (P ⫽ 0.77, log-rank test), but DPs treated with pimobendan
had significantly longer survival times compared with placebo (P ⬍ .02, log-rank test), with a median survival time of 329 days
in the pimobendan group compared with 50 days in the placebo group, and a hazard ratio of 3.4 (95% confidence interval 1.4–
39.8). Pimobendan resulted in significant improvement in heart failure class when added to standard therapy in this group of dogs
with DCM, and may have contributed to improved survival in DPs.
Key words: Calcium-sensitizing agent; Congestive cardiac failure; Doberman Pinscher; English Cocker Spaniel; Heart; Inodilator.
P
imobendan is a benzimidazole-pyridazinone inodilator.
Pimobendan causes venodilation and arteriodilation
via inhibition of phosphodiesterase (PDE) III, and has positive inotropic effects as a result of both PDE III inhibition
(like amrinone and milrinone) and from a calcium-sensitizing effect.1–3 Calcium sensitizers affect the interaction of
calcium with the troponin C complex,3,4 and increase the
extent of contraction for a given cytosolic concentration of
calcium. The effect of increased preload, whereby increased
stretch of the myofilaments results in increased shortening,
may operate via a similar mechanism.5 This inotropic mechanism seems to have advantages, because myocardial energy expenditure is lower than with positive inotropic
agents operating via cyclic adenosine monophosphate
(cAMP).6–9 In skinned myofiber preparations, the rate of
adenosine triphosphatase activity per unit force generated
is unchanged with addition of pimobendan, despite an increase in active tension.10 In studies of human patients,
myocardial oxygen consumption actually may be reduced
with administration of pimobendan.11 Pimobendan also has
favorable effects on left ventricular relaxation and end-diastolic pressure-volume relations.12–15
The positive inotropic effect of pimobendan in dogs has
From the Department of Veterinary Clinical Studies, Royal Dick
School of Veterinary Studies, Summerhall, Edinburgh, UK (Luis Fuentes, Corcoran, French, Schober); and Boehringer Ingelheim, Vetmedica GmbH, Ingelheim am Rhein, Germany (Kleemann, Justus). Dr
Luis Fuentes is presently affiliated with The Ohio State Veterinary
Teaching Hospital, Columbus, OH. Data from this study were presented as an abstract at the British Small Animal Veterinary Association Congress in Birmingham, UK, in 1998.
Reprint requests: Virginia Luis Fuentes, MA, VetMB, PhD, CertVR,
DVC, Dipl ACVIM (Cardiology), The Ohio State Veterinary Teaching
Hospital, 601 Vernon Tharp Street, Columbus, OH 43210; e-mail:
[email protected].
Submitted April 5, 2001; Revised September 4, 2001; Accepted December 18, 2001.
Copyright 䉷 2002 by the American College of Veterinary Internal
Medicine
0891-6640/02/1603-0007/$3.00/0
been demonstrated in a number of studies,9,13,16–19 including
in dogs with myocardial failure, wherein the effect of traditional positive inotropic agents is often blunted.14 The calcium-sensitizing effect of pimobendan may predominate
over the PDE III effect in chronic heart failure, because
down-regulation of the cAMP signaling transduction pathway occurs not only by down-regulation of beta-adrenergic
receptors, but also by increases in the inhibitory subunit of
the G-protein complex20 and activation of ␤-adrenergic receptor kinase,21 thus diminishing the effect of PDE III inhibition.22,23
Pimobendan’s vasodilatory effects occur as a result of
PDE III inhibition, and result in both venodilation and arteriodilation.18,24,25 Studies in dogs after IV administration,
and in human heart failure patients after PO administration,
demonstrate a reduction in filling pressures and systemic
vascular resistance.13,14,18,26–31
Studies of pimobendan in human heart failure patients
have shown an improvement in exercise tolerance and peak
rate of oxygen consumption,26,27,32–35 in contrast with the
inconsistent influence of PDE inhibitors on exercise duration.36,37 Most studies have also shown improvement in
quality of life.32,33,38 Results have been favorable in human
clinical trials comparing treatment with pimobendan and
angiotensin-converting enzyme (ACE) inhibitors,26,34,39 and
additional benefits were seen when pimobendan was added
to background therapy of diuretics, ACE inhibitors, digoxin, and carvedilol.40
This double-blind, placebo-controlled trial was undertaken to examine the effects of pimobendan in dogs with naturally occurring dilated cardiomyopathy (DCM). Because
differences in the clinical course of DCM have been noted
among affected breeds,41 the interpretation of any response
to drug therapy is complex when multiple breeds are involved. Two specific breeds were recruited for this study:
Doberman Pinschers (DPs) and English Cocker Spaniels
(CSs), reflecting 2 breeds with a contrasting clinical course.
DPs have a very poor prognosis, with the majority of dogs
surviving less than 6 months after diagnosis.42,43 The prog-
256
Luis Fuentes et al
Table 1. Modified New York Heart Association (NYHA)
scoring system used to assess functional severity of heart
failure.
NYHA Class
1
2
3
4
Clinical Signs
Evidence of cardiac disease, but no clinical
signs or exercise intolerance.
Evidence of cardiac disease, but no clinical
signs except at exercise. Moderate activity
causes fatigue, dyspnea, or both.
Cardiac disease associated with clinical signs
such as coughing or dyspnea, but comfortable
at rest.
Cardiac disease associated with severe congestive heart failure, such that the animal is exhibiting clinical signs at rest, with little or no
capacity for exercise.
nosis is better in CSs, with some dogs surviving for more
than 4 years after diagnosis.44,45
The aim of this clinical trial was to evaluate the efficacy
and influence of pimobendan on long-term survival in dogs
with DCM, when used in combination with background
therapy of furosemide, enalapril, and digoxin.
Materials and Methods
The study conformed to the Use of Animals (Scientific Procedures)
Act 1986, and informed consent was obtained from each owner.
Subjects
DPs (n ⫽ 10) and CSs (n ⫽ 10) presented with congestive heart
failure resulting from DCM to the Small Animal Clinic, Royal (Dick)
School of Veterinary Studies, were recruited for the study. All dogs
were currently in modified New York Heart Association (NYHA) class
3 or 4 (Table 1), or had been in modified NYHA class 3 or 4 within
the 2 weeks before presentation. Inclusion criteria included echocardiographic confirmation of a dilated, hypocontractile left ventricle in
the absence of marked valvular disease or congenital heart defects,
and radiographic evidence of pulmonary edema. In 3 of the CSs, subjective thickening of the mitral valve leaflets was noted, but all had
an increased left ventricular end-systolic volume index, consistent with
myocardial failure.46,47
The gender distribution in the pimobendan and placebo groups was
similar, with 1 neutered female in both groups of CSs, and 2 neutered
females and 3 males (or neutered males) in each DP group. Median
age was 6 years (3–9 years) in the CS placebo group and 9 years (3–
14 years) in the pimobendan-treated group. Median age was 10 years
(8–10 years) in the DP placebo group and 9 years (6–9 years) in the
pimobendan-treated DPs. At the start of therapy, all CSs were in sinus
rhythm, and 1 DP in the pimobendan group was in atrial fibrillation,
compared with 3 of the placebo-treated DPs. The median NYHA class
was 3.0 (3.0–4.0) in the placebo group, and 3.5 (2.0–4.0) in the pimobendan group.
Concurrent Therapy
Prior therapy with diuretics or ACE inhibitors was not an exclusion
criterion. On entry to the study, all dogs were treated PO with furosemide, enalapril,a and digoxin,b and any additional drugs were withdrawn for at least 10 days. Furosemide was given to effect (2–9 mg/
kg/d PO in divided doses), enalapril was given at 0.5 mg/kg PO q12–
24h, and serum digoxin concentration was confirmed to be in the therapeutic range of 0.6–1.9 ng/mL before commencement of study drug
administration. Mean doses of furosemide, enalapril, and digoxin were
not significantly different for placebo- versus pimobendan-treated dogs
(Table 2). DPs and CSs were randomized separately to receive either
pimobendan (0.3–0.6 mg/kg/d PO) or placebo in addition to standard
triple therapy, according to a double-blind protocol. The randomization
was carried out off-site in blocks of 10 for each breed, by means of
proprietary software,c with the identity of the capsules (whether containing pimobendan or placebo) unknown to anyone attending the
dogs. No dog received any oral drugs during the study period apart
from furosemide, enalapril, digoxin, and either pimobendan or placebo. One CS in the placebo group received topical ear preparations
intermittently throughout the study period.
Study Design
The clinical condition of each subject was evaluated at baseline and
at 3-week intervals for the DPs, and at 6-week intervals for the CSs.
In addition to information on the patient response provided by the
owner, a complete physical examination, 6-lead ECG, thoracic radiographs, and echocardiogram were obtained at each reevaluation. The
major study variables were modified NYHA class and survival time.
Survival times were calculated as the period from the initiation of
pimobendan or placebo treatment until death of the animal, withdrawal
from the study, or the end of the 4-year study period (whichever was
soonest). Withdrawal from the study was evaluated as a fatality even
though survival time may have been longer. Noncardiac causes of
death and euthanasia for intractable heart failure were also treated as
uncensored data.
Statistical Analysis
Results are reported as the mean ⫾ standard deviation (SD), 95%
confidence intervals of the mean (95% CI), or the median value and
range. A Fisher’s exact test was used to assess the response to pimobendan or placebo as binary data (improved/not improved) after addition to treatment with conventional therapy. An improvement was
indicated by attainment of a lower modified NYHA class at any point
during the study period with respect to the NYHA class achieved after
stabilization with conventional therapy. For the comparison of survival
times, Kaplan-Meier curves were constructed and log-rank tests were
used to compare survival curves, with the hazard ratio expressed as
95% CIs. The significance level was set at P ⬍ .05. All statistical
analyses were carried out with proprietary statistical software programs.d,e
Results
Clinical Efficacy
After initiation of standard triple therapy, both groups
improved to a median NYHA class of 2.0 (range in placebo
Table 2. Drug doses at start of trial therapy.
Group
English Cocker Spaniel Placebo
English Cocker Spaniel pimobendan
Doberman Pinscher placebo
Doberman Pinscher pimobendan
Digoxin
(mg/kg/d)
0.011
0.012
0.008
0.009
⫾
⫾
⫾
⫾
0.002
0.003
0.003
0.002
Furosemide
(mg/kg/d)
4.0
4.0
5.7
2.9
⫾
⫾
⫾
⫾
2.0
1.8
2.4
1.1
Enalapril
(mg/kg/d)
0.62
0.59
0.81
0.68
⫾
⫾
⫾
⫾
0.29
0.23
0.29
0.27
Pimobendan in Canine DCM
257
failure class during treatment with pimobendan compared
with placebo (P ⬍ .02). Only 1 of 10 dogs receiving placebo showed further improvement after stabilization with
conventional therapy, whereas 8 of 10 of the dogs receiving
pimobendan showed further improvement at some point
during the study period (P ⫽ .005, Fisher’s exact test).
Two dogs developed diabetes mellitus during the course
of the study: a CS in the placebo group, and a DP in the
pimobendan group. One CS in the placebo group had 2
episodes of witnessed syncope.
Survival
Fig 1. Modified New York Heart Association (NYHA) heart failure
class is shown in 10 dogs treated with pimobendan (A) and 10 dogs
treated with placebo (B) in addition to treatment with furosemide, enalapril, and digoxin (triple). The graphs show heart failure class on 1st
presentation (initial), after stabilization with conventional treatment
(triple), and then the lowest heart failure class achieved during the
study period (triple ⫹ pimobendan/triple ⫹ placebo). The majority of
dogs in both treatment groups improved with conventional therapy,
but only 1 of 10 of the dogs in the placebo-treated group showed
further improvement after initial stabilization. In the pimobendan
group, 8 of 10 dogs showed improvement with the addition of pimobendan to standard therapy (P ⬍ .005, Fisher’s exact test).
group, 2.0–4.0; range in pimobendan group, 2.0–3.0; Fig
1). The median value for the lowest NYHA class attained
at any point during the study period was 2.0 (1.0–4.0) for
the placebo group, and 1.0 (1.0–2.0) for the pimobendantreated group.
No statistical difference was found between placebo and
pimobendan groups for the NYHA class at initial presentation or after conventional therapy, but a Mann-Whitney
rank sum test showed a significant improvement in heart
CSs. Four CSs died during the follow-up period. Three
of these animals were euthanized for noncardiac diseases.
One dog in the placebo group was euthanized with gastrointestinal disease, and 2 dogs were euthanized in the pimobendan group (1 with a nasal tumor, and 1 with fecal
incontinence). One animal in the pimobendan group died
suddenly within 1 month of diagnosis. All other CSs were
still alive at the end of the study period, although 1 dog
from the placebo group was withdrawn from the study with
diabetes mellitus. Median survival according to KaplanMeier analysis (including all-cause mortality and study
withdrawals) was 537 days (range, 61–1,428 days) in the
placebo group and 1,037 days (range, 51–1,127 days) in
the pimobendan group (P ⫽ .77; Fig 2A).
DPs. All DPs died during the study period. Six dogs died
suddenly (3 dogs in each group), and 2 dogs were euthanized with intractable cardiac failure (placebo group). One
dog in the pimobendan group developed immune-mediated
hemolytic anemia that was treated with corticosteroids, and
subsequently developed pancreatitis. Signs of congestive
failure recurred with fluid therapy, and her death was not
observed, so that it was not clear which of the conditions
was primarily responsible for her death. The pimobendantreated DP that developed diabetes mellitus was withdrawn
from the study after 329 days. The pimobendan treatment
was stopped, although he continued with the standard therapy, and was euthanized for congestive failure 2 months
later.
A log-rank test comparing the survival curves showed
significant differences between the placebo- and pimobendan-treated DPs (P ⬍ .02; Fig 2B). The median survival
time for pimobendan-treated DPs was 329 days (range, 42–
393 days), and the median survival time in the placebo
group was 50 days (range, 13–196 days), with a hazard
ratio of 3.4 (95% CI 1.4–39.8).
Discussion
This study examined the effects of pimobendan on dogs
with DCM when added to background therapy of furosemide, enalapril, and digoxin. In both breeds, the addition
of pimobendan to a standard treatment protocol was associated with a significant improvement in functional heart
failure class. Overall, 8 of 10 animals in the pimobendantreated group improved their modified NYHA-class status
during the study period, compared with 1 of 10 animals in
the placebo group. Therefore, pimobendan therapy seemed
to confer additional benefit over the background therapy of
furosemide, enalapril, and digoxin. Although the ages in
258
Luis Fuentes et al
Fig 2. Survival curves for English Cocker Spaniels (A) and Doberman Pinschers (B). No significant difference was found in survival
between the placebo- and pimobendan-treated English Cocker Spaniels, with both groups having relatively long survival times. A significant difference was found in the survival curves between the 2 Doberman Pinscher groups, with the pimobendan group having longer survival times (P ⬍ .02, log-rank test).
the 2 DP groups were similar, a nonsignificant trend towards a younger age was found in the CS placebo group
compared with the CS pimobendan group. Younger age at
diagnosis has been associated with a poorer prognosis in
canine DCM, and may have been a factor in the poorer
response in the CS placebo group compared with the CS
pimobendan group.48
At the end of the 4-year study period, 6 of 10 CSs were
still alive, and 3 of 10 CSs had died of noncardiac disease,
thus confirming previous observations that CSs with DCM
have the potential for long survival times. The lack of obvious benefit on survival times does not exclude the possibility of a potential adverse effect of pimobendan in CSs,
although the study did not have adequate power to assess
this possibility. From the results of this study, any trial undertaking the effect of therapy on the survival of CSs with
DCM clearly would have to be of much longer duration
and include larger numbers of dogs. Although it had been
suspected that survival times might be above average in the
CS group compared with historical controls, the magnitude
of the survival times and the incidence of noncardiac deaths
had not been anticipated.
Although DPs are known to have poor survival times
after development of congestive signs,43,49 a significant improvement in survival was found for pimobendan-treated
animals, with a median survival of 50 days in the placebo
group compared with 329 days in the pimobendan group
(P ⬍ .02, log-rank test).
This finding contrasts with the prevailing attitude to use
of positive inotropic agents in the treatment of chronic heart
failure in human patients, where a number of trials have
revealed adverse effects on survival despite short-term hemodynamic benefits.37,50–52 Even where short-term quality
of life is markedly improved, any increase in mortality is
considered unacceptable in the treatment of human heart
failure.52,53 However, the appropriate use of positive inotropic agents in human patients is an area of controversy, especially because differences may occur in outcome according to dose and whether treatment is short-term, intermittent, or long-term.54–57 The cause of the increased mortality
seen with long-term use of some positive inotropes in human patients is unknown, but may be related to increased
cytosolic calcium concentrations, because increased calcium concentrations predispose to arrhythmia, and may increase the likelihood of sudden death. Additional problems
associated with positive inotropes include increased myocardial energy expenditure, although this is less true of PDE
inhibitors, where the arteriodilating effects may reduce
myocardial workload sufficiently to offset increased energy
consumption from increased contractility.58
Pimobendan was shown to increase survival in cardiomyopathic Syrian hamsters.59 In human patients, studies
have shown reduced numbers of hospitalizations or adverse
events with pimobendan compared with placebo,31,32,60 although no studies have been published of human heart failure patients where survival has been a primary endpoint.
A number of studies that used 24-hour Holter monitoring
failed to demonstrate any proarrhythmic tendencies.31,34,60
The Pimobendan in Congestive Heart Failure (PICO) trial
of 317 patients followed over 6 months was not designed
as a survival study, but showed a nonsignificant trend toward increased mortality in the low-dose group of pimobendan-treated patients.35 However, the number of sudden
cardiac deaths in the high-dose pimobendan group of the
PICO study was identical to that of the placebo group. In
a recent study of patients with nonischemic DCM who were
unable to tolerate beta-adrenergic antagonists, pimobendan
had no adverse effect on survival over 2 years when added
to standard therapy. In this human study, patients treated
with pimobendan in addition to standard therapy had lower
requirements for additional medications for worsening heart
failure, compared with patients receiving standard therapy
and placebo.60 Differences may occur in outcome between
cardiomyopathic patients of ischemic and nonischemic origin, with a more favorable response to pimobendan in the
latter.35,60 Nevertheless, in the absence of any specifically
designed survival trials, whether the effect of pimobendan
on mortality in human heart failure patients differs from
that of other positive inotropic agents is unclear.
The addition of pimobendan to conventional therapy in
DPs in our study resulted in a survival advantage, although
Pimobendan in Canine DCM
the true magnitude of the effect is difficult to assess with
the uneven number of dogs with atrial fibrillation in the 2
groups. The effect on survival in CSs was unclear, because
their survival times in general were so long. The possibility
of a contributory effect to the sudden death of the CS in
the pimobendan group cannot be ruled out, although no
trend was found toward increased sudden death in the DPs.
The effect of positive inotropic agents on survival in dogs
with naturally occurring heart failure has not been critically
evaluated, and the validity of extrapolating from human
survival trials remains unknown. Despite ominous longterm effects in human heart failure patients with ischemic
disease, clinical trials of milrinone appeared very promising
in the treatment of heart failure in dogs,61–64 although the
studies were never extended to long-term, placebo-controlled trials.
Factors possibly were operating that may have adversely
influenced survival in the DP placebo group, contributing
to the differences in survival. The DP placebo group included an increased number of dogs with atrial fibrillation
(3 of 5 dogs, versus 1 of 5 dogs in the pimobendan group).
Atrial fibrillation has been shown to be associated with poor
survival times in DPs with DCM, with a median survival
time of only 2.9 weeks in 1 study.43 In view of this, it would
have been preferable to have a separate randomization
schedule for dogs with atrial fibrillation, because the survival times would be expected to be shorter. The randomization unfortunately resulted in an uneven distribution of
atrial fibrillation cases, which may have unduly affected the
outcome. The trend toward a higher furosemide dose in the
DP placebo group may reflect this. However, the sample
size was too small to allow a subanalysis of the DPs without
the atrial fibrillation cases. Nevertheless, the dog with atrial
fibrillation in the pimobendan group survived for 265 days,
despite having ascites and pleural effusion on initial presentation. The combination of atrial fibrillation and biventricular failure was associated with a particularly poor prognosis in the study by Calvert et al,43 with such dogs having
a median survival time of only 2.0 weeks and a range of
⬍1–13 weeks, yet this DP survived for 37 weeks. With
only 1 DP with atrial fibrillation in the pimobendan group,
knowing if this was a chance effect or related to the pimobendan treatment is difficult. One of the pimobendantreated DPs subsequently developed atrial fibrillation after
being withdrawn from the study (and thus withdrawn from
pimobendan treatment, although continuing with standard
treatment) and 1 of the placebo-treated CSs developed atrial
fibrillation during the course of treatment.
Although some of the benefit seen in the pimobendantreated DP most likely was associated with sustained improvement in hemodynamic function, other factors also
may have played a role. By improving hemodynamic function, pimobendan may have resulted in an indirect reduction
in neurohormonal activation. Several studies have shown a
reduction in neurohormonal activation, with reductions in
plasma norepinephrine levels,28,60 atrial and brain natriuretic
hormones,60 and endothelin-1 levels.40 Also, effects are apparent on proinflammatory cytokines, with reductions reported in tumor necrosis factor ␣ and interleukin (IL)-1b65
and IL-6.40
Whenever euthanized animals are not censored in sur-
259
vival studies, the influence of timing of euthanasia must be
considered. Two of the placebo-treated DPs were euthanized at the request of the owners after developing intractable congestive cardiac failure that did not respond to increasing the dosage of diuretics. Two of the pimobendantreated dogs also developed congestive heart failure during
the study period, but this was after developing anemia and
pancreatitis in 1 dog, and after withdrawal of pimobendan
after development of diabetes mellitus in the other. The
latter dog’s survival time was assessed up to the point of
withdrawal from the study, although he survived a further
2 months on standard triple therapy without pimobendan
before developing a recurrence of congestive signs. In both
cases, development of congestive heart failure was more
than 350 days after entering the study.
No attempt was made to record 24-hour ambulatory
ECGs, or to stratify the risk of fatal arrhythmia. Three sudden deaths occurred in each DP treatment group, and 1
sudden death occurred in the pimobendan-treated CS group,
all of which were assumed to be cardiac.66,67 Although adverse effects on survival were not apparent in this study,
ambulatory ECG recordings would be important in identifying the risk of proarrhythmia associated with pimobendan, and should be considered in a larger study.
Diet was not standardized during the study, although supplementation with taurine and carnitine has been shown to
be helpful in American Cocker Spaniels with DCM.68 Serum or whole blood taurine concentrations were not measured in any of the dogs in this study, although the authors
have previously failed to identify low serum taurine concentrations in any CSs with DCM (unpublished observations).
Blood pressure was not routinely recorded during this
study, although hypotension is a potential risk with severe
DCM, use of ACE inhibitors, and with the vasodilating
effects of pimobendan. Hypotension, if present, did not appear to result in clinical signs.
Although the sample size in this study was small, the
results suggest that pimobendan may be a useful treatment
for dogs with congestive heart failure associated with
DCM. Pimobendan resulted in improvement in functional
heart failure class, and was associated with reduced mortality in the DPs presenting with congestive heart failure in
this study. These results suggest that undertaking a larger
study with a longer duration of follow-up would be worthwhile, to evaluate the effect of pimobendan in a broader
range of dogs with DCM.
Footnotes
Enalapril Cardiovet, Intervet Ltd, Milton Keynes, Bucks, UK
Lanoxin, Greenford, Middlesex, UK
c
SAS, SAS Institute Inc, Cary, NC, USA
d
SigmaStat 2.0, Jandel Scientific, San Rafael, CA, USA
e
Prism, Version 3.0, GraphPad Software, Inc, San Diego, CA, USA
a
b
Acknowledgments
Funding and pimobendan and placebo were provided by
Boehringer Ingelheim Vetmedica GmbH, Ingelheim am
260
Luis Fuentes et al
Rhein, Germany. KDS was supported by a grant from the
German Academic Exchange Service (DAAD), Bonn, Germany.
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