Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 17 DRUGS USED IN THE MANAGEMENT OF HEART DISEASE AND CARDIAC ARRHYTHMIAS
veterinary evaluation of enalapril study) it was shown
that measurements of acute hemodynamic variables in
dogs in heart failure generally did not change but chronic
measures of clinical status did. A second study (COVE:
co-operative veterinary enalapril study group) examined
211 dogs at 19 centers. In this blinded and placebocontrolled
clinical trial, dogs on enalapril again improved
clinically when compared to those on placebo over a
28-day period. There were 141 dogs with primary mitral
regurgitation and 70 with dilated cardiomyopathy as
the primary diagnosis.
A third study (LIVE: long-term investigation of veterinary
enalapril study) continued to examine 148 dogs
from the COVE and IMPROVE studies for up to 15.5
months. Dogs remained in the study until they developed
intractable heart failure (n = 48), died of heart
failure (n = 17), died suddenly (n = 10), died of a noncardiac
cause (n = 4), dropped out of the study for other
reasons (n = 48) or the study ended (n = 21). Dogs
administered enalapril remained in the study significantly
longer (169 days) than dogs administered the
placebo (90 days). Most of this benefit occurred in the
first 60 days. After that, dogs in both groups either
developed intractable heart failure or died at a similar
rate. When divided into dogs with mitral regurgitation
and those with dilated cardiomyopathy, the dogs with
dilated cardiomyopathy receiving enalapril remained in
the study significantly longer than those receiving
placebo while the dogs with mitral regurgitation did
not. Enalapril has been shown to be beneficial in dogs
with mitral regurgitation but of less benefit for the
group as a whole than might have been expected. In
general, some dogs with mitral regurgitation have dramatic
responses to an ACE inhibitor, many improve
clinically but a significant number have little response.
A more recent clinical trial compared the effects of
benazepril to placebo in 162 canine patients (37 with
dilated cardiomyopathy and 125 with primary mitral
regurgitation) with mild to moderate heart failure. Most
dogs were already being treated for heart failure with
diuretics and vasodilators, including other ACE inhibitors.
Benazepril (0.25–0.5 mg/kg/day) increased time to
treatment failure or death (428 days) when compared
to placebo (158 days). The percentage of dogs surviving
without being withdrawn from the study because of
worsening heart failure 1 year after the onset of the
study was 49% in the benazepril group and 20% in the
placebo group. From these data it appears that benazepril
produces benefits similar to other ACE inhibitors
in dogs with heart failure.
The results of these studies are quite clear. ACE inhibitors,
despite the fact that they produce minimal hemodynamic
change, result in clinical improvement in dogs
with heart failure due to mitral regurgitation or dilated
cardiomyopathy. ACE inhibitors appear to perform
better in dogs with DCM but are clearly efficacious in
many dogs with mitral regurgitation. However, in
general and in both diseases, the clinical response is not
profound. Rather, in most cases ACE inhibition results
in mild and gradual improvement, which helps to stabilize
the clinical course of the patient and improve the
quality of life.
More recently, pimobendan has been demonstrated
to be superior to a variety of ACE inhibitors for the
treatment of canine heart failure (see p. 398). Based on
all currently available data it is one of the author’s
(Gordon) opinion that optimum canine heart failure
therapy from 2007 involves a combination of an ACE
inhibitor and pimobendan as well as furosemide at a
dose that controls signs of congestion.
Preclinical cardiovascular disease
Studies have been performed in humans to determine if
starting ACE inhibitor therapy with enalapril in patients
with left ventricular dysfunction but without evidence
of heart failure is beneficial. Benefit has been defined as
reduction in mortality, reduction in the incidence of
heart failure and reduction in the hospitalization rate.
In a study of human patients with chronic cardiac
disease, 4228 patients with ejection fractions less than
35% (comparable to a shortening fraction below 15%)
were randomized to receive either placebo or enalapril.
They were followed clinically for an average of 37
months. During this time there was no reduction in
mortality associated with enalapril administration.
There was a reduction in the incidence of heart failure
and in hospitalizations for heart failure (the drug delayed
the onset of heart failure). These latter findings should
be expected for any drug meant to effectively treat heart
failure.
A recent study examined the effects of administering
either enalapril or placebo to 237 cavalier King Charles
spaniels with myxomatous mitral valve disease and
mitral regurgitation over 2 years. Dogs at entry had to
have a heart murmur due to mitral regurgitation, with
or without radiographic evidence of cardiomegaly.
Enalapril, when compared to placebo, had no effect on
how soon these dogs went into heart failure. Consequently,
there is no current indication for administering
an ACE inhibitor to dogs with mitral regurgitation prior
to the development of heart failure. These results were
more recently confirmed in an all breed study.
Adverse effects
The potential risks of interfering with angiotensin II
formation lie in its role of preserving systemic blood
pressure and glomerular filtration rate (GFR) as renal
flow decreases. Blocking angiotensin II action on peripheral
arterioles can result in hypotension that leads
to cerebral hypoperfusion. Dizziness is seen in 15%
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