Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
INODILATORS
EXAMPLES
Oral: pimobendan
IV: milrinone, amrinone
This class of agents has both positive inotropic and
vasodilatory properties and they have been labeled inodilators
as a reflection of the term ‘inodilation’ (coined
by Lionel H Opie in 1989). Historically, short-term
management of acute or decompensated heart failure
characterized by systolic dysfunction benefited from a
combination of dobutamine (inotrope) and sodium
nitroprusside (vasodilator). Agents in this class combine
these properties but are not as potent as a combination
of dobutamin and nitroprusside. However, pimobendan
is available in an oral formulation, making chronic
therapy possible.
Pimobendan
Clinical applications
Pimobendan is a novel agent with properties that are
desirable in the clinical management of canine heart
failure secondary to both DCM and chronic CVD in
dogs.
The efficacy of pimobendan in the treatment of heart
failure arising from DCM and CVD has been evaluated
thoroughly in dogs. Available prospective data support
its ability to significantly reduce morbidity in dogs with
heart failure secondary to these conditions. A prospective
blinded placebo-controlled study by O’Grady et al
demonstrated a doubling of overall survival in Doberman
pinschers with heart failure secondary to DCM,
from a mean of 63 ± 14 days (mean ± standard deviation)
with furosemide, an ACE inhibitor and placebo,
to 128 ± 29 days with furosemide, an ACE inhibitor
and pimobendan at 0.25 mg/kg by mouth twice daily (P
= 0.04). Additional studies suggest a survival benefit
with the combination of pimobendan and furosemide
when compared to an ACE inhibitor and furosemide
(with or without digoxin) in dogs with heart failure
secondary to DCM or CVD.
Other studies offer conflicting evidence with respect
to the superiority of pimobendan over an ACE inhibitor
for the treatment of heart failure secondary to CVD.
Preliminary analysis of an ongoing study by O’Grady
et al showed no survival advantage using pimobendan
and furosemide compared to an ACE inhibitor and
furosemide in dogs with heart failure due to CVD. Conversely,
Smith et al and Lombard et al (VetScope study)
demonstrated superiority of a combination of pimobendan
and furosemide over an ACE inhibitor (ramipril or
benazepril respectively) and furosemide for the treat-
ment of heart failure due to CVD. Smith’s study reported
a significant reduction of overall adverse outcomes,
including death from the CHF (euthanized or died) and
treatment failure when furosemide and ramipril (48%)
were compared to furosemide and pimobendan (18%)
over 6 months of treatment. Lombard’s study reported
that the median survival (i.e. death or treatment failure)
for dogs receiving pimobendan and furosemide was 415
days versus 128 days for those receiving benazepril and
furosemide (P = 0.0022). In all three studies no significant
adverse consequences occurred, which suggests
that the combination of pimobendan and furosemide is
superior to furosemide and an ACE inhibitor for the
treatment of heart failure due to CVD.
To date, pimobendan appears to be safe and well
tolerated in dogs with heart failure associated with
CVD. Pimobendan in combination with an ACE inhibitor
and furosemide has not been prospectively evaluated
in comparison to an ACE inhibitor and furosemide in
heart failure due to CVD. However, when used with
concurrent therapy such as furosemide, an ACE inhibitor,
digoxin, spironolactone, etc., it appears to be
beneficial.
One of the authors (Gordon) has been using pimobendan
(0.25–0.3 mg/kg PO) in addition to background
heart failure therapy for > 6 years in over 300 dogs for
the treatment of CHF from both DCM and CVD. In
one unpublished study from these 300 dogs, survival
and hemodynamic effects were reviewed in a subset of
dogs with advanced heart failure due to CVD. In addition
to pimobendan these dogs received furosemide
(100%, at least 3 mg/kg PO q.12 h) and an ACE inhibitor
(100%), spironolactone (>75%), a β-blocker (20%),
digoxin (11%) and hydrochlorothiazide (3%). Hemodynamic
effects were evaluated prior to initiation of
pimobendan and approximately 45 days later. No significant
changes in indirect systemic blood pressures,
bodyweight, hematocrit, total solids, serum creatinine
or electrolytes (P = 0.05) were detected. Blood urea
nitrogen concentration increased significantly in some
dogs (pre-pimobendan 29 mg/dL vs post-pimobendan
33 mg/dL, P < 0.05). Heart rate and respiratory rate
were reduced and no changes occurred in the combined
frequency of arrhythmias (i.e. ventricular premature
beats, ventricular tachycardia, supraventricular premature
beats, supraventricular tachycardia and atrial fibrillation)
on electrocardiograms. A trend (P = 0.059) was
noted in reduction of the dosage of furosemide administered
to the dogs.
Certain echocardiographic parameters suggested
improvement in systolic function, namely a reduction in
left ventricular (LV) internal dimension in systole,
reduction of LV end-systolic area and an increase in
the percentage of LV area shortening. Reduction in the
regurgitant fraction was suggested by a decrease in the
398