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THERAPY OF CONGESTIVE HEART FAILURE IN DOGS WITH
INODILATORS
Christophe W. Lombard,
Prof. DACVIM (Cardiology),
DECVIM-CA
The recent two decades have seen revolutionary
changes in the concept of treating congestive
heart failure in man and animals. The recognition
of overshooting neuroendocrine mechanisms,
in particular excessive activation of the reninangiotensin-aldosterone system (RAAS) with
increased angiotensin-II levels elevating afterload
and stimulating excessive myocardial hypertrophy
(cardiac remodelling), is now well established,
Increased afterload damages an already failing
heart even further. Inhibitors of the angiotensinconverting enzyme (ACE-inhibitors) have been
developed to counteract these adaptations and
have proven their efficacy for treating congestive
heart failure in man and in dogs. They have
also demonstrated efficacy in combination
with digoxin and diuretics. Additionally, ACEinhibitors have shown to prolong survival in man,
and in dogs with endocardiosis with mitral and/
or tricuspid insufficiency compared to placebocontrols on conventional therapy. Efficacy- and
improved survival data have been published for
enalapril (the COVE trial 1995, the LIVE trial
1998) and for benazepril (the BENCH trial 1999).
Increasing contractile function of the failing heart
in cardiomyopathy continues to be a goal for
therapeutic intervention (Endoh 2001). Attention
has focused on drugs using other than direct
stimulation via adrenergic receptors and the
adenylate cyclase pathway. Phosphodiesterase
III-inhibitors such as milrinone are potent
positive inotropes, but their regrettable side
effect of increasing mortality in humans through
arrhythmogenesis (the “PROMISE” trial, Packer
et al 1991) prevented their successful registration
and release for treatment.
The recent development of inodilator drugs
has addressed this problem in an elegant and
successful way. These substances utilise a new
mode of action, the sensitisation of cardiac
troponin C to calcium, to improve contractility.
Such compounds are referred to as “Calcium
– Sensitizers” and have been described to have
a positive impact on myocardial energetics
(Hasenfuss et al 1989, Remme et al 1994). The
ideal positive inotropic drug should have some
negative chronotropic effects, should be mediated
by other than increases in calcium transients,
and should decelerate cross-bridge kinetics
(Holubarsch 1997). Mixtures of the d- and lisomers of Pimobendan were shown to cause
stereospecific increases of the calcium sensitivity
of cardiac myofilaments, specifically at the
regulatory calcium binding sites of troponin C
(Solaro et al 1989), besides having vasodilatatory
properties mediated by the phosphodiesterase IIIeffects on vascular smooth muscle. The inodilator
drug Pimobendan has been used successfully
for the treatment of heart failure in humans in
Japan (Kato, 1997). A recent study revealed
significantly less adverse cardiac events, defined
as death or hospitalisation due to heart failure,
in human patients under Pimobendan therapy
(EPOCH Study Group, 2002). Clinical studies
performed in dogs revealed an efficacy at doses
between 0.2 to 0.6 mg/kg/day (Kleemann and
others 1998a), as well as clearly superior clinical
benefits over digoxin (Kleemann et al 1998b,
Poulsen Nautrup et al 1998). In these studies,
dogs with chronic valvular disease (endocardiosis
with mitral and/or tricuspid regurgitation) as
well as dilated cardiomyopathy in advanced
stages of heart failure were included. They
improved their clinical condition under therapy.
Furthermore, Pimobendan was shown to clearly
and highly significantly prolong the survival time
in a small number of Dobermans with dilated
cardiomyopathy, increasing the median survival
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2006 World Congress WSAVA/FECAVA/CSAVA
Dept. of clinical veterinary
medicine
Vetsuisse Faculty, University of
Berne
Länggass-Strasse 124, PO Box
CH-1201 Bern/Switzerland
[email protected]
23
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2006 World Congress WSAVA/FECAVA/CSAVA
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time from 50 days to 329 days (Luis Fuentes et
al 2002).
We are going to review the major blinded,
placebo-controlled multicenter studies of the last
few years that have investigated the efficacy of
Pimobendan for the treatment of congestive heart
failure in dogs. Some of the above-mentioned
investigations and data led to the licensing of
Pimobendan for the therapy of canine CHF in
the majority of European countries over last few
years, an achievement that no other veterinary
drug can claim so far.
The PiTCH-Study is a multicenter randomised
positive-controlled study that was conceived
in the late 90ies and tested the concept that
dogs in congestive heart failure due to mitral
regurgitation or dilated cardiomyopathy could
be treated with either Pimobendan, Benazepril or
both drugs together with the additional diuretic
Furosemide where needed due to pulmonary
congestion. 105 Dogs with moderately to severe
CHF were included and blindly randomised to
one of the 3 treatment groups. The initial efficacy
study period over 28 days revealed a significantly
higher drop-out rate of 34% for the Benazepril
group vs. 11% for the Pimobendan group and 9%
for the combination group. On a clinical scoring
system based on signs such as dyspnea/cough,
nocturnal restlessness, appetite, general activity
etc. both groups with Pimobendan outperformed
the Benazepril group. The combination of
Pimobendan with Benazepril did not provide
significant better results than Pimobendan alone.
A voluntary longevity study followed, during
which the dogs could receive, upon request of
the owner when their dogs deteriorated, the drug
that they hadn’t gotten before as an addition to
their therapy. The survival time was determined
until such addition of drug or death or euthanasia
occurred and compared Benazepril-treated
dogs against dogs receiving Pimobendan alone
or both drugs. A significantly longer survival
time resulted for the dogs on Pimobendan. This
study contained several weaknesses, namely an
(unnecessary) combination-TX group and an
unfortunately small number of dogs with mitral
regurgitation that lead to small group numbers
preventing meaningful statistical evaluation and
power of the study.
The Vetscope study is a multicenter doubleblinded
trial which sought to compare the advantages of
Pimobendan against Benazepril in dogs with
moderately to severe congestive heart failure
(ISACHC-classes 2 and 3) due to valvular
disease/mitral regurgitation. A total of 76 dogs
were enrolled. The study parameters and the setup were similar to the PiTCH-study. Furosemide
was allowed and used equally (ca. 2/3 of the
cases) in both treatment groups.
Overall efficacy was rated as very good or good
in 85% of the Pimobendan cases versus 41% of
the Benazepril cases (P<0.0001). In the 56-Day
study period, 2 dogs in the Pimobendan group
and 7 in the Benazepril group died or were
euthanised due to cardiac reasons. The group
mean of radiographically determined heart size
diminished in the Pimobendan group, while it
increased slightly in the Benazepril group (p =
0.0329). Survival analysis according to KaplanMeier for the 56-day period revealed significant
differences in favour of Pimobendan (P=0.0386).
Median survival time for Pimobendan treated
dogs was 430 days versus 228 days for dogs
receiving no Pimobendan. Again, survival
analysis according to Kaplan-Meier revealed
significant differences in favour of pimobendan
(P=0.002). The complete study report will appear
in the Journal of the American Animal Hospital
Association in the summer of this year 2006.
Another study by Smith et al 2005 evaluated 43
dogs suffering from mitral regurgitation and mild
to moderately severe congestive heart failure in
a prospective randomised, single-blind parallelgroup trial against Ramipril over a study period
of 6 months. All dogs received variable dosages
of Furosemide. Study endpoints were were
completion of the entire study period, and the
need for hospitalisation and therapy adjustment
in case of worsening. Pimobendan treated
dogs completed the study in higher numbers
(68%) than Ramipril-treated dogs (43%), and
Pimobendan-treated dogs also had a significantly
lower adverse HF-outcome (18%) than Ramipriltreated dogs (48%, p= 0.046 calculated as an odds
ratio). Tolerance, i.e. drug-related sideeffects, of
Pimobendan was low and comparable to Ramipril,
as it had been in comparison to Benazepril in the
studies above.
All 3 studies did not reveal any tendency to
increased tachyarrhythmias or heart rate elevation,
although ECGs had only been measured over max.
5 minutes, rather than by Holter electrocardiography for convincing proof of the absence of
arrhythmogenesis of this drug.
General remarks and conclusions
The new inodilator or calcium-sensitiser drug
Pimobendan has shown convincing evidence of
good tolerability, safety and clinical efficacy in
randomised, blinded multicenter clinical trials; it
proved statistically superior to the ACE-inhibitors
Benazepril and Ramipril when analysing clinical
parameters, and prolonged survival significantly.
The drug showed these desired effects in both of
the most common canine cardiac diseases dilated
cardiomyopathy and mitral regurgitation due to
chronic valvular disease, in moderate to severe
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References
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2006 World Congress WSAVA/FECAVA/CSAVA
stages of congestive heart failure. It appears
therefore that this new drug represents a new
pillar in the heart failure therapy of dogs. What
remains to be tested are its safety and efficacy
when applied in less severe stages of heart failure,
convincing evidence of non-arrhythmogenesis,
and elucidation of its influence on pathologic
remodelling of the heart during these diseases.
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