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Electrocardiographic Changes in Dogs with Degenerative Mitral Valve Disease Treated with Pimobendan: a Retrospective Study of 29 Cases

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Abstract

The aim of this retrospective study was to evaluate changes in electrocardiograms (ECG) and cardiac arrhythmias in 29 dogs with degenerative mitral valve disease (DMVD) treated with pimobendan chronically. All dogs had normal ECG before pimobendan administration. The dogs were classified according to ECG after pimobendan administration into 2 groups: normal ECG (n=19) and abnormal ECG (n=10). Age, sex, breed, serum alkaline phosphatase, concurrent digoxin administration, total daily dosage of pimobendan and digoxin, duration of pimobendan administration, and ECG parameters including heart rate, P wave, PR interval, QRS complex, and QT interval were analyzed. Cardiac arrhythmias were increasingly found in the dogs treated with pimobendan in combination with digoxin. The total daily dosage of pimobendan and digoxin in the dogs with abnormal ECG was higher than in those with normal ECG (p=0.022, 0.038, respectively). In conclusion, cardiac arrhythmias can be found in dogs chronically treated with pimobendan. Therefore, caution should be taken when using pimobendan at a high dosage or in combination with digoxin.
Thai J Vet Med. 2016. 46(2): 243-249.
Electrocardiographic Changes in Dogs with Degenerative Mitral
Valve Disease Treated with Pimobendan:
a Retrospective Study of 29 Cases
Sirilak Disatian Surachetpong1* Nisarat Boonlue2 Pasorn Pupa2 Waratsarin Boonsathitanan2
Sumanee Rakthaidee2 Tanawan Mangklabruks3 Siriwan Sakarin4
Abstract
The aim of this retrospective study was to evaluate changes in electrocardiograms (ECG) and cardiac
arrhythmias in 29 dogs with degenerative mitral valve disease (DMVD) treated with pimobendan chronically. All dogs
had normal ECG before pimobendan administration. The dogs were classified according to ECG after pimobendan
administration into 2 groups: normal ECG (n=19) and abnormal ECG (n=10). Age, sex, breed, serum alkaline
phosphatase, concurrent digoxin administration, total daily dosage of pimobendan and digoxin, duration of
pimobendan administration, and ECG parameters including heart rate, P wave, PR interval, QRS complex, and QT
interval were analyzed. Cardiac arrhythmias were increasingly found in the dogs treated with pimobendan in
combination with digoxin. The total daily dosage of pimobendan and digoxin in the dogs with abnormal ECG was
higher than in those with normal ECG (p=0.022, 0.038, respectively). In conclusion, cardiac arrhythmias can be found
in dogs chronically treated with pimobendan. Therefore, caution should be taken when using pimobendan at a high
dosage or in combination with digoxin.
Keywords: arrhythmia, canine, digoxin, pimobendan
1Department of Veterinary Medicine, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand
26th year student, Academic year 2014, Faculty of Veterinary Science, Chulalongkorn University, Bangkok 10330, Thailand
3Clinic for Small Domestic Animals and Radiology, Faculty of Veterinary Medicine, Mahanakorn University of Technology,
Bangkok 10530, Thailand
4Master degree student, Academic year 2014, Faculty of Veterinary Science, Chulalongkorn University,Bangkok 10330, Thailand
*Correspondence: sirilakd27@gmail.com
Original Article
244 Surachetpong S. et al. / Thai J Vet Med. 2016. 46(2): 243-249.
Introduction
Several studies in human patients reported
that some of the positive inotropic agents might have
pro-arrhythmic effects (Felker and OConnor, 2001;
Packer et al., 1991). In veterinary medicine, studies
evaluating pro-arrhythmic effects of positive inotropic
drugs are scarce. Presently, positive inotropes such as
pimobendan and digoxin have been widely prescribed
in dogs with congestive heart failure, including the
most common disease, degenerative mitral valve
disease (DMVD) (Summerfield et al., 2012; Haggstrom
et al., 2013a; Kanno et al., 2007).
Pimobendan (4,5 dihydro-6-[2- (4-
mrthoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-
3(2H)-pyridazinone), a benzimidazole-pyridazinone
derivative, increases the myocardium contractility by
inhibiting phosphodiesterase 3 and 4 enzymes,
decreasing an elimination of cyclic adenosine 3,5-
monophosphate (cyclic AMP), and ultimately
increasing calcium within the cytosol of the
myocardium. Pimobendan also enhances the
myocardial contractility without an increase in
myocardial oxygen demand by augmenting the
sensitivity of troponin C to calcium, which is called the
calcium sensitizing property (Fitton and Brogden,
1994). This property of pimobendan is different from
cardiac glycosides such as digoxin and catecholamines
(Matos and Glaus, 2010). Moreover, pimobendan acts
as a vasodilator by increasing the cyclic AMP within
the endothelial cells, facilitating calcium uptake
through intracellular storage sites, thereby decreasing
the amount of calcium available for contraction,
resulting in vasodilation (McDaniel et al., 1994). It has
been believed that pimobendan has a low calcium-
mediated pro-arrhythmic effect because pimobendan
acts as a calcium sensitizer with a minimal effect on an
increase in calcium concentration in the myocardium
(Ruegg, 1986). Nowadays studies evaluating pro-
arrhythmic effects of pimobendan are sparse and
conflicting. A previous study reported that
pimobendan had an acute effect on
electrophysiological properties of the myocardium and
atrioventricular (AV) node (Kitzen et al., 1988). Human
patients treated by pimobendan had a trend toward
higher risk of sudden death, presumably secondary to
cardiac arrhythmias (Felker and OConnor, 2001;
Lubsen et al., 1996). An adverse effect of pimobendan
inducing cardiac arrhythmias in giant dog breeds has
been suggested (Rosenthal et al., 2006). Several studies
reported evidence of cardiac arrhythmias in dogs
treated with pimobendan; however, the frequency and
incidence of arrhythmias were not different when
compared with dogs treated with the other drug,
benazepril (Haggstrom et al., 2008; Haggstrom et al.,
2013a). A short-term pilot study did not find any
significant difference in the incidence or types of
arrhythmia between degenerative mitral valve disease
(DMVD) dogs treated with pimobendan and a placebo
(Lake-Bakaar et al., 2015). However, most of these
studies were performed over limited time periods, i.e.
not more than 2 months, and were not designed for
evaluating a pro-arrhythmic effect of pimobendan. To
the authors knowledge, a long-term effect of
pimobendan on cardiac arrhythmias in dogs with heart
diseases has not been studied yet. Therefore, the aim of
this study was to evaluate long-term effects of
pimobendan on electrocardiographic changes and
cardiac arrhythmias in dogs affected by DMVD.
Materials and Methods
From February 2010-November 2014, clinical
data on dogs diagnosed with DMVD stage C at the
Cardiology Clinic, Small Animal Veterinary Teaching
Hospital, Chulalongkorn University, Thailand were
studied. The dogs had been diagnosed with DMVD by
an echocardiographer (SS) and staged using the
American College of Veterinary Internal Medicine
(ACVIM) classification (Atkins et al., 2009).
Echocardiography, radiography, and
electrocardiography (ECG) were performed on the day
of the DMVD diagnosis before the administration of
pimobendan. All the dogs were treated with
pimobendan at an average dosage of 0.39±0.15 mg/kg
per day. Data on the patients including age, sex,
weight, breed, alkaline phosphatase levels, concurrent
use of digoxin, total daily dosage of pimobendan and
digoxin, duration of pimobendan administration, ECG
before and after treatment with pimobendan, and time
of pimobendan treatment before the occurrence of
arrhythmias were collected. Electrocardiographic
records obtained from a three-minute Lead II tracing
were evaluated. Duration and amplitude of P wave,
QRS complex, and T wave as well as PR and QT
intervals were measured randomly and averaged from
10 consecutive waves. QT and corrected QT (QTc)
intervals were measured and calculated, using Van de
Water’s equation QTc = (QT - 0.087 * [(60 / HR) - 1]
(Van de Water et al., 1989). Dogs with abnormal ECG
prior to pimobendan treatment were excluded from
the study. Newly diagnosed cardiac arrhythmias after
treatment with pimobendan were recorded.
Statistical analysis
Statistical analyses were performed using a
commercial statistical software (Minitab®17, State
College, PA, USA). The patient data including age, sex,
weight, breed, and alkaline phosphatase levels were
reported descriptively. Normality of the data was
tested by the Shapiro-Wilk. Normally distributed data
were presented as mean±standard deviation (SD). In
dogs with normal ECG after pimobendan
administration, ECG parameters including P wave,
QRS complex, T wave durations and amplitudes, and
duration of PR and QTc intervals were compared
before and after pimobendan treatment by a paired t
test. Effects of the treatment duration, breeds of dogs,
and concurrent use of digoxin on an evidence of ECG
abnormalities were evaluated by Fishers exact test.
The dosage per day of pimobendan and digoxin and
the treatment duration of dogs with normal and
abnormal ECG after pimobendan treatment were
compared by an unpaired t-test. Differences at p-value
<0.05 were considered significant.
Results
The data of twenty-nine dogs met the
inclusion criteria. Nineteen dogs had normal ECG and
ten dogs had abnormal ECG after treated with
Surachetpong S. et al. / Thai J Vet Med. 2016. 46(2): 243-249. 245
pimobendan. The information on the dogs is
summarized in Table 1.
In the dogs with normal ECG after treated
with pimobendan, there was no difference in the P
wave, QRS complex, T wave durations and
amplitudes, and duration of PR and QTc intervals
before and after being treated with pimobendan alone
(Table 2) and pimobendan in combination with
digoxin (Table 3).
The data of dogs with abnormal ECG after
being treated with pimobendan are summarized in
Table 4. Eight of the ten dogs had increased alkaline
phosphatase after being treated with pimobendan.
Only three dogs had higher levels more than five times
of normal limits.
Table 1 Information on 29 dogs included in the study
Total dogs (n=29)
Dogs with normal ECG after
treated with pimobendan (n=19)
Dogs with abnormal ECG after
treated with pimobendan
(n=10)
Age (year)*
12.9±2.5
13.3±2.7
12.3±2.2
Weight (Kg)*
7.4±5.6
6.2±4.6
9.6±6.7
Sex
Male=18 (62.1%)
Female=11 (37.9%)
Male=11 (57.9%)
Female=8 (42.1%)
Male=7 (70.0%)
Female=3 (30.0%)
Small breeds
21 (72.4%)
Shih Tzu (8), Poodle (7),
Miniature pinscher (2), Splitz (1),
Pekingese (1), Pomeranian (1),
Chihuahua (1)
15 (78.9%)
Shih Tzu (6), Poodle (4), Miniature
Pinscher (2), Splitz (1), Pekingese
(1), Chihuahua (1)
6 (60.0 %)
Poodle (3), Shih Tzu (2),
Pomeranian (1)
Middle breeds
8 (27.6%)
Mixed (6), Bangkeaw (1), Basset
hound (1)
4 (21.1%)
Mixed (3), Basset hound (1)
4 (4.0%)
Mixed (3), Bangkeaw (1)
Digoxin
14 (48.3%)
15 (51.7%)
6 (31.6%)
13 (68.4%)
8 (80.0%)
2 (20.0%)
Dosage (mg/kg/d)
0.39±0.15
0.007±0.002
(n=14)
0.35±0.15
0.005±0.001
(n=6)
0.47±0.12
0.008±0.003
(n=8)
*Data presented as mean±standard deviation (SD)
Table 2 Comparison of electrocardiography before and after treated with pimobendan alone in DMVD dogs with normal ECG
(n=13)
Before
After
p-value
Heart rate (b/m)
116±23
126±23
0.12
P wave
Amplitude (mV)
Duration (sec)
0.29±0.11
0.05±0.01
0.26±0.12
0.04±0.01
0.49
0.16
PR interval (sec)
0.09±0.03
0.10±0.04
0.51
QRS complex
Amplitude (mV)
Duration (sec)
1.99±0.95
0.04±0.03
1.71±0.62
0.04±0.06
0.30
0.34
QTc interval (sec)
0.16±0.06
0.16±0.08
0.56
Data presented as mean±standard deviation (SD)
Table 3 Comparison of electrocardiography before and after treated with pimobendan in combination with digoxin in dogs with
normal ECG (n=6)
Before
After
p-value
Heart rate (b/m)
134±26
131±21
0.81
P wave
Amplitude (mV)
Duration (sec)
0.32±0.09
0.04±0.01
0.25±0.13
0.04±0.01
0.39
0.36
PR interval (sec)
0.10±0.03
0.12±0.01
0.61
QRS complex
Amplitude (mV)
Duration (sec)
2.08±0.46
0.05±0.02
1.84±0.58
0.04±0.01
0.29
0.26
QTc interval (sec)
0.19±0.11
0.18±0.02
0.78
Data presented as mean±standard deviation (SD)
Five dogs were treated with pimobendan for
a month. Two out of these dogs had abnormal ECG.
Eight of fourteen dogs treated with pimobendan for
more than a month had abnormal ECG. Six of the
twenty-one small breeds and four of the eight middle
breeds had abnormal ECG. There was no effect of the
246 Surachetpong S. et al. / Thai J Vet Med. 2016. 46(2): 243-249.
treatment duration (30 days versus >30 days) (p=0.211)
and breed (small versus middle breeds) (p=0.348) on
the development of abnormal ECG. The duration of
pimobendan administration was not different between
the dogs with normal ECG (202±47 days) and
abnormal ECG (333±74 days) (p=0.155). The dogs
treated with pimobendan in combination with digoxin
had a higher risk of developing abnormal ECG than the
dogs treated with pimobendan alone (p=0.013) (Table
1). The dogs with abnormal ECG were treated with a
higher dosage per day of digoxin and pimobendan
than the dogs with normal ECG (p=0.038, p=0.022,
respectively) (Table 1).
Table 4 Information on dogs with abnormal electrocardiography after treated with pimobendan
Age
(year)
Breed
Digoxin
Duration of
pimobendan
supplementation
(month)
Alkaline
phosphatase
Electrocardiography
Severe LA
enlargement
(LA:Ao
ratio>2)
Before
After
Before receiving
pimobendan
After receiving
pimobendan
16
Shih Tzu
N
1
254
65
Respiratory
arrhythmia
2nd degree AV
block
Y
11
Poodle
N
1
63
104
Sinus rhythm
Atrial
fibrillation
Y
11
Bangkeaw
Y
2
102
65
Respiratory
arrhythmia
Junctional
premature beat
N
13
Mixed
Y
5
19
36
Sinus rhythm
Atrial
fibrillation
with VPCs
Y
13
Poodle
Y
8
184
353
Sinus rhythm
2nd degree AV
block
N
14
Mixed
Y
10
148
735
Sinus rhythm
Sinus
tachycardia*
N
14
Poodle
Y
14
107
223
Sinus rhythm
Sinus
tachycardia*
N
11
Mixed
Y
14
86
159
Respiratory
arrhythmia
Sinus
tachycardia*
N
12
Pomeranian
Y
15
78
190
Sinus rhythm
Atrial
fibrillation
N
8
Shih Tzu
Y
16
264
319
Respiratory
arrhythmia
Atrial
fibrillation
Y
LA=Left atrium; Ao=aorta; Y=yes; N=no
*Sinus tachycardia was defined as heart rate more than 200 beat/min.
Discussion
The major finding of this study is that cardiac
arrhythmias can be found in dogs chronically treated
with pimobendan, especially in dogs treated with a
higher dosage of pimobendan and/or in combination
with digoxin.
The earliest time to detect cardiac
arrhythmias in the population of dogs in this study was
a month after the pimobendan treatment. Types of
cardiac arrhythmias included atrial fibrillation, sinus
tachycardia, second degree AV block, ventricular
premature beat, and junctional premature beat. These
arrhythmias were similar to the evaluation study of
safety and effectiveness of pimobendan (Vetmedin,
2007). The majority of dogs with cardiac arrhythmias
in the present study had atrial fibrillation. The
mechanism of pimobendan-induced atrial fibrillation
has not been reported. Severe left atrial enlargement
may be a potential cause of atrial fibrillation in 3 of 4
dogs in the present study. It is possible that atrial
fibrillation may occur secondarily to the disease
progression rather than being a direct effect of
pimobendan itself. Pimobendan has a dose-dependent
increase in heart rate secondary to an increase in
intracellular cAMP in cardiac tissues (Hagemeijer,
1993; Chu et al., 1995). One study reported severe sinus
tachycardia in dogs administered with a high dose of
pimobendan (Reinker et al., 2012). Three dogs in the
present study had sinus tachycardia (heart rate >200
beats/min) after approximately a year of treatment
with pimobendan. In contrast, several studies failed to
report the evidence of pimobendan-induced sinus
tachycardia (Smith et al., 2006; Haggstrom et al., 2013b).
Second degree AV block and junctional premature beat
in three dogs in the present study may occur
secondarily to the effect of pimobendan on function of
the AV node (Kitzen et al., 1988). One dog in the
present study had ventricular premature complex
(VPC). It has been concerned that phosphodiestase III
inhibitors like pimobendan may exacerbate the
development of ventricular arrhythmias (Lynch et al.,
1988; Rosenthal et al., 2006). However, a recent study
could not find difference in VPCs number/24 h
between dogs treated with pimobendan and a placebo
(Lake-Bakaar et al., 2015). Several studies
demonstrated that there was no difference in VPC
numbers and incidence of ventricular arrhythmias
when compared between dogs treated with
pimobendan and angiotensin converting enzyme
(ACE) inhibitors (Smith et al., 2006; O’Grady et al.,
2004). Based on the results of those previous studies,
the effect of pimobendan-induced VPCs is still
controversial. In the present study, some dogs with
abnormal ECG had high levels of alkaline phosphatase
after being treated with pimobendan. According to the
safety study, pimobendan can cause a mild elevation
of alkaline phosphatase levels (Vetmedin, 2007). It has
Surachetpong S. et al. / Thai J Vet Med. 2016. 46(2): 243-249. 247
been suggested that alkaline phosphatase may increase
due to a major elimination pathway of pimobendan
through bile excretion (Plumb, 2008).
Presently, there are few studies determining
the pro-arrhythmic effects of pimobendan in
veterinary medicine. A previous study showed that
dogs treated with higher doses of pimobendan had a
higher risk of developing cardiac arrhythmias
(Summerfield et al., 2012). Similarly, the present study
showed that the dogs with abnormal ECG were treated
with a higher dosage of pimobendan than those with
normal ECG. However, the present study failed to
show the effect of breed (small versus medium breeds)
on pimobendan-induced cardiac arrhythmias. A
previous study showed that giant dog breeds had a
higher risk of developing cardiac arrhythmias after
treatment with pimobendan (Rosenthal et al., 2006).
Unfortunately, none of the giant breeds was included
in the present study.
The dogs treated with pimobendan in
combination with digoxin had a higher risk of
developing cardiac arrhythmias than those treated
with pimobendan alone. The dogs with cardiac
arrhythmias were also treated with a higher dosage of
digoxin. Digoxin itself can cause cardiac arrhythmias
secondary to its toxicity (Steiness and Olesen, 1976).
However, all dogs developing cardiac arrhythmias in
this study had digoxin levels (1.5±0.5 ng/ml) within
the normal limit (0.5- 2 ng/ml) and presented no sign
of digoxin toxicity, e.g. diarrhea, anorexia, and
vomiting. Presently, there was no report studying the
synergist effect of pimobendan and digoxin on
induced cardiac arrhythmias. In theory, pimobendan
may increase the rate of intestinal digoxin absorption
(Aiba et al., 2005). However, clinically, there is no
report evaluating the effects of pimobendan on digoxin
absorption or serum digoxin concentration.
Because the study was retrospective, there
were several limitations that could not be controlled.
Firstly, the present study was performed without a
control group; thus, the effect of worsening disease
severity was not accounted for. Arrhythmias might
develop without the effects of pimobendan. Secondly,
the monthly follow-up might delay or miss the
detection of cardiac arrhythmias in some dogs before
the appointment. Thirdly, the data were collected from
a small number of dogs, not enough to extrapolate the
whole population of dogs. Thus, a prospective study
evaluating the long-term effect of pimobendan on ECG
changes and electrophysiology with a larger number of
dogs should be performed. Lastly, Holter monitoring
was not done in the present study. With 3-minute ECG
tracings, cardiac paroxysmal arrhythmias might not be
detected in some dogs.
In conclusion, cardiac arrhythmias may
develop in some dogs treated chronically with
pimobendan, especially in dogs treated with a higher
dosage of pimobendan and/or in combination with
digoxin. ECG monitoring should be performed in dogs
chronically administered with pimobendan.
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


สิริลักษณ์ สุรเชษฐ์พงษ์1,* นิศารัตน์ บุญลือ2 ภาษร ภูผา2 วรัสศริณ บุญสถิตอนันต์2 สุมณี รักไทยดี2
ธนวัน มังคละพฤกษ์3 ศิริวรรณ สาครินทร์4
 

   n= 
 n=
  
  
  p=, 0.038  


:    
110330
26 2557 10330
310530
42557 10330
*ผู้รับผิดชอบบทความE-mail: sirilakd27@gmail.com
249
... Studies focused on other standard therapy drugs (pimobendan or ACE inhibitors, such as the QUEST and the EPIC studies [370,371], respectively, which focused on symptomatic and asymptomatic dogs with cardiac remodeling) or drugs used in case of complications related to this syndrome (such as β-blockers, amlodipine, and digoxin) [372][373][374][375][376][377][378][379][380][381][382][383][384] have also been published. In the QUEST and EPIC studies, pimobendan was administered over a dose range of 0.4 to 0.6 mg/kg/daily and benazepril over a dose range of 0.25 to 1 mg/kg/daily. ...
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The treatment of chronic congestive heart failure (CHF), secondary to myxomatous mitral valve disease (MMVD) in dogs, has considerably changed in the last fifty years. An analysis of the literature concerning the therapy of chronic CHF in dogs affected by MMVD is not available, and it is needed. Narrative reviews (NRs) are aimed at identifying and summarizing what has been previously published, avoiding duplications, and seeking new study areas that have not yet been addressed. The most accessible open-access databases, PubMed, Embase, and Google Scholar, were chosen, and the searching time frame was set in five decades, from 1970 to 2020. The 384 selected studies were classified into categories depending on the aim of the study, the population target, the pathogenesis of MMVD (natural/induced), and the resulting CHF. Over the years, the types of studies have increased considerably in veterinary medicine. In particular, there have been 43 (24.29%) clinical trials, 41 (23.16%) randomized controlled trials, 10 (5.65%) cross-over trials, 40 (22.60%) reviews, 5 (2.82%) comparative studies, 17 (9.60%) case-control studies, 2 (1.13%) cohort studies, 2 (1.13%) experimental studies, 2 (1.13%) questionnaires, 6 (3.40%) case-reports, 7 (3,95%) retrospective studies, and 2 (1,13%) guidelines. The experimental studies on dogs with an induced form of the disease were less numerous (49–27.68%) than the studies on dogs affected by spontaneous MMVD (128–72.32%). The therapy of chronic CHF in dogs has considerably changed in the last fifty years: in the last century, some of the currently prescribed drugs did not exist yet, while others had different indications.
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The benefit of pimobendan in delaying the progression of preclinical dilated cardiomyopathy (DCM) in Dobermans is not reported. That chronic oral administration of pimobendan to Dobermans with preclinical DCM will delay the onset of CHF or sudden death and improve survival. Seventy-six client-owned Dobermans recruited at 10 centers in the UK and North America. The trial was a randomized, blinded, placebo-controlled, parallel group multicenter study. Dogs were allocated in a 1:1 ratio to receive pimobendan (Vetmedin capsules) or visually identical placebo. The composite primary endpoint was prospectively defined as either onset of CHF or sudden death. Time to death from all causes was a secondary endpoint. The proportion of dogs reaching the primary endpoint was not significantly different between groups (P = .1). The median time to the primary endpoint (onset of CHF or sudden death) was significantly longer in the pimobendan (718 days, IQR 441–1152 days) versus the placebo group (441 days, IQR 151–641 days) (log-rank P = 0.0088). The median survival time was significantly longer in the pimobendan (623 days, IQR 491–1531 days) versus the placebo group (466 days, IQR 236–710 days) (log-rank P = .034). The administration of pimobendan to Dobermans with preclinical DCM prolongs the time to the onset of clinical signs and extends survival. Treatment of dogs in the preclinical phase of this common cardiovascular disorder with pimobendan can lead to improved outcome.
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Myxomatous mitral valve disease (MMVD) continues to be an important cause of morbidity and mortality in geriatric dogs despite conventional therapy. Pimobendan in addition to conventional therapy will extend time to sudden cardiac death, euthanasia for cardiac reasons, or treatment failure when compared with conventional therapy plus benazepril in dogs with congestive heart failure (CHF) attributable to MMVD. Two hundred and sixty client-owned dogs in CHF caused by MMVD were recruited from 28 centers in Europe, Canada, and Australia. A prospective single-blinded study with dogs randomized to PO receive pimobendan (0.4-0.6 mg/kg/d) or benazepril hydrochloride (0.25-1.0 mg/kg/d). The primary endpoint was a composite of cardiac death, euthanized for heart failure, or treatment failure. Eight dogs were excluded from analysis. One hundred and twenty-four dogs were randomized to pimobendan and 128 to benazepril. One hundred and ninety dogs reached the primary endpoint; the median time was 188 days (267 days for pimobendan, 140 days for benazepril hazard ratio = 0.688, 95% confidence limits [CL]=0.516-0.916, P= .0099). The benefit of pimobendan persisted after adjusting for all baseline variables. A longer time to reach the endpoint was also associated with being a Cavalier King Charles Spaniel, requiring a lower furosemide dose, and having a higher creatinine concentration. Increases in several indicators of cardiac enlargement (left atrial to aortic root ratio, vertebral heart scale, and percentage increase in left ventricular internal diameter in systole) were associated with a shorter time to endpoint, as was a worse tolerance for exercise. Pimobendan plus conventional therapy prolongs time to sudden death, euthanasia for cardiac reasons, or treatment failure in dogs with CHF caused by MMVD compared with benazepril plus conventional therapy.
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Background: Pimobendan and benazepril are frequently used with diuretics to treat dogs in congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). Aim: Jo compare the short-term effects of pimobendan versus benazepril on pump function, heart size and neuroendocrine profile in dogs with CHF caused by MMVD. Animals: Sixteen client-owned dogs. Materials and methods: Seven-day prospective single-blinded study of dogs stabilized on furosemide monotherapy, randomized to pimobendan (0,4-0,6 mg/kg/day) or benazepril (0,25-1,0 mg/kg/day). Dogs had first-pass radionuclide angiocardiography, and heart size was measured by radiography and echocardiography. Circulating neuroendocrine hormones were measured. Results: Baseline variables did not differ between treatment groups. Greater decreases in the pimobendan than in the benazepril group were found for heart rate (P=.001), heart rate-normalized pulmonary transit time (P=.02), left atrial size (P=.03), and systolic and diastolic left ventricular diameters (P<.001 and P=.03, respectively) and volumes (P<.001 and P=.02, respectively), whereas ejection fraction increased more (P=.02) in the pimobendan group. Of the neuroendocrine hormones, only N-terminal proatrial natriuretic peptide (NT-ProANP) differed (P=.04) between groups. Within groups, plasma aldosterone increased (P=.01), and NT-proANP (P=01) and NT-proB-type (P=.01) decreased in the benazepril group. Conclusions and Clinical Importance: Pimobendan improves short-term cardiac function more than benazepril in dogs with CHF caused by MMVD. Pimobendan treatment enables the heart to work at smaller end-systolic and diastolic dimensions while maintaining adequate forward stroke volume. Some of the treatment response found in neuroendocrine profile might have therapeutic relevance.
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To determine if pimobendan, a phosphodiesterase III inhibitor and calcium sensitizer with positive survival benefits, has an effect on incidence of arrhythmias compared to placebo in small breed dogs with congestive heart failure (CHF) due to myxomatous mitral valve degeneration (MMVD). Eight client-owned small breed dogs (<15 kg) with CHF due to MMVD. A prospective double-blind randomized placebo-controlled crossover study design was used. Data were recorded at baseline and 2 weeks post-administration of placebo or pimobendan. Average heart rate and incidence of arrhythmia were determined from 24 h Holter analysis. Owners completed a quality of life (QOL) questionnaire at each time point and recorded sleeping respiratory rates (SRR). Mixed effects analysis of variance, with dog as the random variable was used to compare values obtained between baseline, placebo, and pimobendan. Compared to baseline, QOL scores were significantly improved following administration of either placebo or pimobendan (p = 0.021 and p < 0.001, respectively). No significant differences in type or incidence of supraventricular or ventricular arrhythmia were identified. Average heart rate with pimobendan was significantly lower than baseline (p < 0.001). Compared to baseline, SRR was significantly lower with pimobendan (p = 0.004), and significantly different from placebo (p = 0.045). No significant difference between pimobendan and placebo was found on incidence of supraventricular or ventricular arrhythmia. The decrease in average heart rate and SRR may be reflective of superior heart failure control achieved with pimobendan therapy. Published by Elsevier B.V.
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Synopsis Pimobendan is a novel cardiotonic vasodilator (inodilator) which derives its inotropic activity from a combination of phosphodiesterase III inhibition and sensitisation of myocardial contractile proteins to calcium. The acute haemodynamic benefits of pimobendan (2.5 to 10mg orally; 5 to 10mg intravenously) seen in patients maintained on conventional diuretic, digitalis and vasodilator therapy for chronic heart failure (increases in cardiac output and stroke volume, and reductions in left ventricular preload and afterload) persisted on short term (1 month) therapy, and showed only limited evidence of attenuation on longer term (6 months) oral therapy with pimobendan 2.5 or 5mg twice daily. Adjunctive therapy with pimobendan 1.25 to 5mg twice daily for periods of 3 to 6 months improved exercise tolerance on symptom-limited exercise testing, New York Heart Association (NYHA) functional class, and quality of life, and additionally reduced the need for hospitalisation in patients with moderate to severe chronic heart failure. Pimobendan appears to be well tolerated at therapeutic doses (1.25 to 5mg twice daily) in patients with chronic heart failure, and preliminary indications suggest that it is largely devoid of the proarrhythmic effects of classical phosphodiesterase III inhibitors. Although information regarding the long term effects of pimobendan on mortality is currently lacking, the drug nevertheless shows potential benefit as an adjunctive therapy in patients with chronic heart failure.
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Pimobendan and benazepril are frequently used with diuretics to treat dogs in congestive heart failure (CHF) caused by myxomatous mitral valve disease (MMVD). To compare the short-term effects of pimobendan versus benazepril on pump function, heart size, and neuroendocrine profile in dogs with CHF caused by MMVD. Sixteen client-owned dogs. Seven-day prospective single-blinded study of dogs stabilized on furosemide monotherapy, randomized to pimobendan (0.4-0.6 mg/kg/day) or benazepril (0.25-1.0 mg/kg/day). Dogs had first-pass radionuclide angiocardiography, and heart size was measured by radiography and echocardiography. Circulating neuroendocrine hormones were measured. Baseline variables did not differ between treatment groups. Greater decreases in the pimobendan than in the benazepril group were found for heart rate (P = .001), heart rate-normalized pulmonary transit time (P = .02), left atrial size (P = .03), and systolic and diastolic left ventricular diameters (P < .001 and P = .03, respectively) and volumes (P < .001 and P = .02, respectively), whereas ejection fraction increased more (P = .02) in the pimobendan group. Of the neuroendocrine hormones, only N-terminal proatrial natriuretic peptide (NT-ProANP) differed (P = .04) between groups. Within groups, plasma aldosterone increased (P = .01), and NT-proANP (P = .01) and NT-proB-type (P = .02) natriuretic peptide decreased in the pimobendan group, and NT-proANP (P = .02) and plasma vasopressin (P = .01) decreased in the benazepril group. Pimobendan improves short-term cardiac function more than benazepril in dogs with CHF caused by MMVD. Pimobendan treatment enables the heart to work at smaller end-systolic and diastolic dimensions while maintaining adequate forward stroke volume. Some of the treatment responses found in neuroendocrine profile might have therapeutic relevance.
Article
Myxomatous mitral valve disease (MMVD) is an important cause of morbidity and mortality in dogs. To compare, throughout the period of follow-up of dogs that had not yet reached the primary endpoint, the longitudinal effects of pimobendan versus benazepril hydrochloride treatment on quality-of-life (QoL) variables, concomitant congestive heart failure (CHF) treatment, and other outcome variables in dogs suffering from CHF secondary to MMVD. A total of 260 dogs in CHF because of MMVD. A prospective single-blinded study with dogs randomized to receive pimobendan (0.4-0.6 mg/kg/day) or benazepril hydrochloride (0.25-1.0 mg/kg/day). Differences in outcome variables and time to intensification of CHF treatment were compared. A total of 124 dogs were randomized to pimobendan and 128 to benazepril. No difference was found between groups in QoL variables during the trial. Time from inclusion to 1st intensification of CHF treatment was longer in the pimobendan group (pimobendan 98 days, IQR 30-276 days versus benazepril 59 days, IQR 11-121 days; P = .0005). Postinclusion, dogs in the pimobendan group had smaller heart size based on VHS score (P = .013) and left ventricular diastolic (P = .035) and systolic (P = .0044) dimensions, higher body temperature (P = .030), serum sodium (P = .0027), and total protein (P = .0003) concentrations, and packed cell volume (P = .030). Incidence of arrhythmias was similar in treatment groups. Pimobendan versus benazepril resulted in similar QoL during the study, but conferred increased time before intensification of CHF treatment. Pimobendan treatment resulted in smaller heart size, higher body temperature, and less retention of free water.
Article
The purpose of this study was to review the medical records of dogs that were either suspected or known to have ingested large doses of pimobendan and to describe the clinical signs associated with pimobendan toxicosis. The database of Pet Poison Helpline, an animal poison control center located in Minneapolis, MN, was searched for cases involving pimobendan toxicosis from Nov 2004 to Apr 2010. In total, 98 cases were identified. Of those, seven dogs that ingested between 2.6 mg/kg and 21.3 mg/kg were selected for further evaluation. Clinical signs consisted of cardiovascular abnormalities, including severe tachycardia (4/7), hypotension (2/7), and hypertension (2/7). In two dogs, no clinical signs were seen. Despite a wide safety profile, large overdoses of pimobendan may present risks for individual pets. Prompt decontamination, including emesis induction and the administration of activated charcoal, is advised in the asymptomatic patient. Symptomatic and supportive care should include the use of IV fluid therapy to treat hypotension and address hydration requirements and blood pressure and electrocardiogram monitoring with high-dose toxicosis. Practitioners should be aware of the clinical signs associated with high-dose pimobendan toxicosis. Of the dogs reported herein, all were hospitalized, responded to supportive care, and survived to discharge within 24 hr of exposure.