A preliminary report on the use of warfarin in the treatment of navicular disease


Colles, C.M.

Equine Veterinary Journal 11(3): 187-190

1979


Horses (20) suffering from navicular disease were treated with warfarin given orally. The dosage was to give a 2-4 s prolongation of the 1 stage prothrombin time (OSPT). Dosage was initially at a rate of 0.018 mg/kg, changing the dose by amounts of 20% until the required dose was achieved. Final dose rates varied from 0.012-0.75 mg/kg. All the cases treated received warfarin daily throughout the trial. Of the animals 17 became sound and the remaining 3 showed a marked improvement in their gait. The mean of the ages of the horses was 7.5 yr, the mean of the periods of lameness 9 mo. and the mean of the time taken to recovery once treatment was commenced was 7 wk.

EQUINE
VETERINARY
JOURNAL
187
Equine
vet.
J.
(1979),
11
(3),
187-190
A
preliminary
report
on
the
use
of
Warfarin
in
the
Treatment
of
Navicular
Disease
C.
M.
COLLES
Equine
Research
Station
of
the
Animal
Health
Trust,
PO
Box
5,
Balaton
Lodge,
Snailwell
Road,
Newmarket,
Suffolk
CB8
7DW
SUMMARY
Twenty
horses
suffering
from
navicular
disease
were
treated
with
warfarin
given
orally.
The
dosage
was
to
effect,
to
give
a
2
to
4
second
prolongation
of
the
one
stage
prothrombin
time
(OSPT).
Dosage
was
initially
at
a
rate
of
0.018
mg/kg,
changing
the
dose
by
amounts
of
20
per
cent
until
the
required
dose
was
achieved.
Final
dose
rates
varied
from
0.012
mg/kg
to
0.75
mg/kg.
All
the
cases
treated
received
warfarin
daily
throughout
the
trial.
Seventeen
of
the
animals
became
sound
and
the
remaining
3
showed
a
marked
improvement
in
their
gait.
The
mean
of
the
ages
of
the
horses
was
7.5
years,
the
mean
of
the
periods
of
lameness
9
months
and
the
mean
of
the
time
taken
to
recovery
once
treatment
was
commenced
was
7
weeks.
INTRODUCTION
REEKS
(1925)
claimed
that
the
clinical
and
pathological
signs
of
"navicular
disease"
had
been
described
as
early
as
1752.
By
1830
the
lameness
was
attributed
to
ulcerations
and
erosions
of
the
fibrocartilage
of
the
navicular
bone,
and
sometimes
lesions
involving
the
deep
digital
flexor
tendon
(Youatt,
1836).
Recent
work
(Colles,
1979)
has
shown
that
the
cartilage
lesions
are
in
fact
seldom
the
cause
of
lameness,
which
is
attributable
to
ischaemia
caused
by
arterial
thrombosis
within
the
navicular
bone
(Colles
and
Hickman,
1977).
Colles
(1979)
suggested
that
tendon
involvement
was
secondary
to
areas
of
ischaemic
necrosis
in
the
bone
immediately
under
the
flexor
surface.
The
overlying
fibrocartilage
then
collapses
under
the
pressure
of
the
tendon
and
a
deep
lesion
is
formed
in
the
flexor
surface
of
the
bone.
He
maintained
that
these
areas
of
necrosis
themselves
resulted
from
arterial
thrombosis.
The
treatment
of
navicular
disease
to
date
has
been
largely
empirical
or
palliative
and
has
been
based
on
the
assumption
that
the
condition
is
arthritic
in
nature.
It
has
generally
been
accepted
that
no
treatment
will
do
more
than
alleviate
signs
or
delay
the
progress
of
the
disease
for
a
limited
period.
Colles
and
Hickman
(1977)
suggested
that
lameness
was
due
to
ischaemia,
but
that
initially
the
periosteum
could
provide
an
adequate
secondary
blood
supply
to
the
navicular
bone.
How-
ever,
if
the
periosteum
also
became
involved
in
thrombosis,
then
a
progressive
ischaemia
of
the
bone,
with
resultant
lameness,
would
occur.
In
view
of
this
recent
work,
it
was
felt
that
therapy
using
anticoagulants
might
have
some
benefit
in
early
cases
of
navicular
disease,
by
allowing
an
adequate
secondary
blood
supply
to
develop
from
the
periosteum.
MATERIALS
AND
METHODS
Clinical
details
Twenty
cases
of
navicular
disease
referred
to
the
Equine
Research
Station
were
available
for
treatment.
The
diagnosis
was
based
on
the
following
criteria:—
The
animal
was
suffering
from
a
progressive,
bilateral
forelimb
lameness
of
one
or
more
month's
standing.
When
trotted
in
hand
on
both
hard
and
soft
sur-
faces,
a
bilateral
shortening
of
the
anterior
phase
of
the
forelimb
gait
was
seen.
Infiltration
of
local
anaesthetic
around
the
medial
and
lateral
posterior
digital
nerves
in
one
foot
eliminated
lameness
on
that
foot.
Radiographic
examination
revealed
a
change
in
shape
of
at
least
2
distal
nutrient
foramina
in
the
navicular
bones.
No
other
clinical
or
radiographic
abnormalities
could
be
detected
that
might
account
for
the
lameness.
The
animals
ranged
in
age
from
2
to
12
years
and
had
been
lame
for
periods
of
between
1
month
and
3
years.
They
included
a
variety
of
breeds
and
were
used
for
several
different
purposes
(Table
I).
During
the
initial
stages
of
treatment
all
20
horses
were
housed
in
looseboxes
and
exercise
was
given
daily,
the
amount
depending
on
the
severity
of
lameness.
Animals
with
very
severe
lameness
were
turned
out
to
graze
during
the
day
and
as
lameness
improved,
they
were
walked
in
hand,
lunged
or
ridden
daily.
Ridden
exercise
initially
consisted
of
20
to
30
min
walking
and
trotting
and
was
gradually
extended
over
6
weeks
to
1
or
12
hours
188
EQUINE
VETERINARY
JOURNAL
TABLE
I
DETAILS
OF
THE
FIRST
20
CASES
OF
NAVICULAR
DISEASE
TREATED
USING
WARFARIN
ORALLY
Case
No
Type
Breed
Age
Period
of
lameness
prior
to
treatment
Period
of
treatment
before
regaining
soundness
1
Hunter
TB
9
years
3
months
2
Hunter
x
TB
8
12
5
weeks
3
Hunter
Half
bred
7
8
4
4
Showpony
Welsh
x
5
1
9
9„
3
5
Hunter
x
TB
10
12
15
6
Showjumper
TB
7
,,
18
10
7
Flat
racer
TB
3
f
t
1
1
71
8
Hunter
TB
x
Percheron
12
5
4
9
Unbroken
Anglo-Arab
3
2
6
10
Showjumper
x
TB
9
8
6
11
Eventer
TB
8
3
2
12
Carriage
horse
Hungarian
TB
9
,,
18
10
13
Police
horse
Irish
10
36
Still
improving
14
Child's
pony
Pony
x
12
6
8
weeks
15
Hunter
x
TB
4
6
7
16
Eventer
x
TB
6
6
2
17
Show
hunter
x
TB
6
1
9,
2
18
Hack
x
TB
10
12
14
19
Police
horse
Irish
8
6
4
20
Showjumper
x
TB
8
6
2
Mean
7.7
8-9
5-7
TB
=
Thoroughbred
of
walking,
trotting
and
cantering.
The
majority
of
animals
were
kept
at
the
Equine
Research
Station
for
6
weeks,
but
6
of
the
early
cases
were
kept
for
longer
periods.
Feeding
was
determined
by
the
amount
of
work
each
horse
was
doing
and
by
the
diet
normally
fed
at
home.
As
far
as
possible
the
diet
was
not
changed,
other
than
in
quantity,
while
the
horses
were
receiving
treatment.
Warfarin
dosage
Warfarin
was
given
daily,
dissolved
in
a
small
amount
of
water
and
added
to
the
horse's
evening
feed.
A
commercial
preparation
of
warfarin
("Marevan"—
Duncan,
Flockhart
&
Co
Ltd)
marketed
for
human
use
was
used.
The
dose
rate
was
determined
individually
for
each
animal.
In
order
to
do
this
the
normal
one
stage
prothrombin
time
(OSPT)
of
the
blood
was
established
for
each
animal,
usually
on
2
occasions.
Warfarin
was
then
given
at
a
dose
rate
of
0.018
mg/kg
and
blood
samples
taken
twice
weekly
for
OSPT
estimations.
If
satisfactory
prolongation
of
the
OSPT
was
not
achieved
after
10
days,
the
dose
of
warfarin
was
adjusted
until
the
desired
time
was
achieved.
The
dosage
was
changed
by
amounts
of
20
per
cent
of
the
current
total
dose.
In
the
early
cases
warfarin
was
given
at
a
dosage
sufficient
to
double
the
OSPT.
During
treatment
of
Case
4,
however,
the
animal
responded
before
this
time
was
reached.
In
later
cases,
therefore,
the
time
was
increased
by
only
2
to
4
seconds.
If
the
clinical
response
was
unsatisfactory,
the
time
was
then doubled.
In
the
initial
stages
of
treating
a
horse,
blood
samples
were
checked
twice
weekly
until
3
consecutive
OSPT's
gave
results
within
1
second
of
each
other.
The
horse
then
returned
home
and
samples
were
taken
at
1,
2
and
4
weeks
after
returning
home.
Subsequently
samples
were
taken
at
4-
to
8-weekly
intervals,
depending
on
the
apparent
stability
of
the
OSPT
for
each
individual
animal.
Laboratory
examinations
The
OSPT
was
determined
using
the
method
described
by
Biggs
and
Macfarlane
(1962),
but
using
equine
brain
thromboplastin
prepared
at
the
Equine
Research
Station
by
the
method
of
Biggs
and
Macfarlane
(1962).
Blood
samples
for
the
test
were
taken
into
sodium
citrate,
7.2
ml
of
blood
being
added
to
0.8
ml
of
3.8
per
cent
tri-sodium
citrate
(Analar,
BDH
Chemicals,
Poole,
Dorset).
It
was
found
that
samples
sent
through
the
post
gave
reproduceable
results
for
4
to
5
days
(Colles,
unpublished
data),
providing
they
were
not
refrigerated
or
heated
and
that
whole
blood
rather
than
serum
was
transported.
Routine
haematological
examinations
were
carried
out
on
hospitalised
animals
twice
weekly
and
biochemical
tests
for
serum
proteins,
aminoaspartate
transferase
(AAT),
creatinekinase
(CPK)
and
bilirubin
were
carried
out
every
14
days.
RESULTS
The
dosage
of
warfarin
needed
to
prolong
the
OSPT
by
2
to
4
seconds
in
the
20
clinical
cases,
and
in
an
additional
12
experimental
animals,
varied
from
0.012
mg/kg
to
0.057
mg/kg
(Fig
1).
No
changes
in
haematological
or
chemicopathological
parameters
were
detected.
EQUINE
VETERINARY
JOURNAL
189
Case
6
was
complicated
by
very
extensive
sidebone
35
30
+
formation
in
both
feet.
This
horse
never
became
completely
sound
on
warfarin
alone.
Concurrent
dosage
of
1
gram
of
butazolidone
daily,
however,
gave
complete
remission
of
the
symptoms.
25—
Case
13
had
been
severely
lame
for
3
years
and
although
markedly
improved,
it
has
failed
to
achieve
complete
soundness
6
months
after
commencing
treatment.
+
++
++
In
each
case
an
OSPT
of
over
2
minutes
was
present
at
On
3
occasions
haematomas
formed
during
treatment.
the
time
the
haematomas
formed.
In
Case
1
it
was
10—
necessary
to
cease
therapy
before
the
haematomas
regressed.
In
Case
2
a
haematoma
formed
on
one
hock
5
+
+
in
the
second
week
of
treatment.
This
was
controlled
E
c
20
15
t+
4-
+
+
4-
+44-
+
+
+
In
all
the
20
cases
treated,
once
a
stable
prolongation
of
the
OSPT
was
achieved,
some
improvement
in
the
lameness
was
seen
within
2
to
3
weeks.
This
improve-
ment
of
gait
was
not
a
steady
process.
Frequently
a
marked
improvement
was
preceded
by
5
to
10
days
of
no
apparent
change,
or
even
increased
lameness.
Seven-
teen
of
the
animals
returned
to
complete
soundness
in
between
1
and
15
weeks
from
the
start
of
treatment.
The
relationship
between
age,
duration
of
lameness
and
time
to
recovery
can
be
expressed
by
the
equation
:—
TH
=
0.76
(0.41
x
D)
+
(0.29
x
A)
±
2.5
where
TH
=
the
time
to
recovery
in
weeks
D
=
the
duration
of
lameness
in
months
A
=
the
age
of
the
animal
in
years.
Five
cases
have
shown
periods
of
transient
lameness
after
becoming
sound.
Two
of
these
received
no
warfarin
for
a
period.
The
others
showed
a
return
of
the
OSPT
to
normal
and
on
increasing
the
dosage
of
warfarin,
the
lameness
disappeared.
All
the
animals
which
have
become
sound
have
returned
home
and
have
been
worked
normally.
Several
have
been
hunted
and
competed
with
no
apparent
adverse
affects.
In
only
3
cases
was
a
complete
return
to
soundness
not
achieved:—
Case
1
was
treated
initially
for
36
days
and
showed
considerable
improvement
in
its
action.
On
the
36th
day
it
became
cast
in
its
loosebox
and
developed
several
haematomas
over
the
shoulders
and
quarters.
The
therapy
was
stopped
immediately
and
the
haematomas
regressed
within
the
next
2
weeks;
however,
the
lameness
returned
to
its
previous
severity.
Treatment
was
recommenced
3
days
later
for
a
further
29
days.
The
animal
again
showed
considerable
regression
of
the
lameness
and
had
recovered
sufficiently
to
indulge
in
bouts
of
bucking
and
kicking
while
being
lunged.
During
one
of
these
escapades
it
developed
a
haemarthrosis
of
one
fetlock.
Treatment
was
again
abandoned
and
over
the
next
7
days
the
lameness
rapidly
returned.
No
further
treatment
was
attempted
and
no
further
follow-up
was
obtainable
as
the
animal
was
sold.
by
applying
an
elastic
bandage
to
the
hock
and
reducing
the
warfarin
dosage.
The
haematoma
resolved
satis-
factorily.
In
subsequent
cases
the
prolongation
of
the
OSPT
had
been
more
effectively
controlled
and
no
further
problems
of
this
nature
have
occurred.
DISCUSSION
Because
of
the
clinical
nature
of
this
work,
it
has
not
been
possible
to
carry
out
control
treatments.
Wintzer
(1964),
however,
reported
on
the
treatment
of
580
cases
of
navicular
disease.
His
treatments
included
neurectomy,
injection
of
cortisone
into
the
navicular
bursa,
the
use
of
anabolic
steroids,
X-irradiation
therapy
and
surgical
shoeing.
Of
his
cases,
only
60
(10.5
per
cent)
were
alive
a
year
later
and
only
26
(4.5
per
cent)
were
described
as
sound.
He
concluded
that
none
of
these
treatments
was
any
more
successful
than
any
other.
Colles
and
Hickman
(1977)
showed
that
the
radiolucent
shadows
visible
on
X-ray
at
the
borders
of
the
navicular
bone
were
inpouchings
of
the
periosteum,
forming
a
secondary
or
supplementary
blood
supply.
They
sug-
gested
that
the
primary
arteries
to
the
navicular
bone
and
this
secondary
blood
supply
become
involved
in
a
progressive
thrombosis
before
lameness
is
evident.
If
this
theory
of
pathogenesis
is
true,
then
treatment
with
anticoagulants
is
a
rational
line
of
therapy,
allowing
the
secondary
blood
supply
to
the
bone
to
develop.
Although
there
are
reports
of
several
anticoagulants
being
used
in
the
horse
(Archer,
1961;
Archer,
Close
and
Ashford,
1969),
warfarin
sodium
(one
of
the
dicoumarol
group)
probably
represents
the
most
practical
anticoagulant
for
clinical
use.
It
is
a
cheap
drug
which
can
be
given
orally
and
has
a
specific
antidote
in
vitamin
K,.
Apart
from
effects
relating
to
blood
clotting,
side-effects
are
rare,
although
foetal
death
has
been
recorded
in
women
receiving
warfarin
therapy.
Little
is
known
about
the
pharmacokinetics
of
warfarin
in
the
horse.
In
man,
97
per
cent
of
the
warfarin
in
the
plasma
is
bound
to
protein
(O'Reilly,
Aggler
and
Leang,
1963)
and
a
similar
situation
is
thought
to
occur
in
other
animals.
This
means
that
the
concurrent
use
of
drugs
that
compete
for
the
protein-binding
sites
(eg,
phenylbutazone)
may
release
a
quantity
of
"active"
warfarin
into
the
blood
stream
and
thus
cause
a
marked
prolongation
of
the
OSPT.
Any
substance
affecting
the
liver
metabolism
(such
as
changes
in
diet)
may
cause
a
change
in
the
rate
of
the
production of
the
clotting
factors,
and
thus
lengthen
or
shorten
the
OSPT.
In
addition
to
this,
there
is
little
known
about
the
inter-
action
of
drugs
with
warfarin
in
the
horse
or
other
250
300
350
400
450
500
550
600
650
700
Weight
(kg)
Fig
1.
Figure
to
show
the
final
dose
of
warfarin
given
to
32
horses
to
establish
an
adequate
stabilised
prolongation
of
the
one
stage
prothrombin
time.
190
EQUINE
VETERINARY
JOURNAL
animals.
Great
care
should
be
taken
when
considering
concurrent
medication,
since
drug
interaction,
as
well
as
overdosage,
may
result
in
haemarthrosis
or
haemorrhage
which
may
prove
fatal.
It
is
still
too
early
for
long
term
follow-up
information
on
many
of
the
cases
treated,
but
the
findings
with
this
treatment
have
been
very
encouraging.
At
the
time
of
going
to
print
2
animals
have
been
sound
for
over
a
year
and
the
remainder
for
an
average
of
6
months.
Over
30
cases
have
been
treated,
all
of
which
have
shown
marked
improvement
with
therapy.
At
the
present
time,
no
case
that
has
become
sound
has
redeveloped
lameness
due
to
"navicular
disease"
while
receiving
adequate
doses
of
warfarin.
ACKNOWLEDGEMENTS
This
forms
part
of
a
PhD
thesis
to
be
submitted
by
the
author
to
the
University
of
London.
I
would
like
to
thank
the
many
veterinary
surgeons
in
practice
who
have
referred
cases
for
examination
and
treatment.
Also
the
staff
of
the
Equine
Research
Station
for
their
assistance
with
the
work
and
the
preparation
of
this
paper.
REFERENCES
Archer,
R.
K.
(1961).
Studies
on
the
coagulation
defect
pro-
duced
by
sodium
warfarin
in
the
horse.
Proc.
7th
Cong.
Europe.
Soc.
Haemat.
London
12,
867-870.
Archer,
R.
K.,
Close,
M.
and
Ashford,
A.
(1969).
The
anti-
coagulant
effect
of
Arvin
on
horse
blood.
Equine
vet.
J.
1,
161-164.
Biggs,
R.
and
Macfarlane,
R.
G.
(1962).
Human
blood
coagulation,
p
158-159.
3rd
Ed.
Blackwell
Scientific
Publications,
Oxford.
Colles,
C.
M.
(1979).
Ischaemic
necrosis
of
the
navicular
bone
(distal
sesamoid
bone)
of
the
horse
and
its
treatment.
Vet.
Rec.
104,
133-137.
Colles,
C.
M.
and
Hickman,
J.
(1977).
The
arterial
supply
of
the
navicular
bone
and
its
variation
in
navicular
disease.
Equine
vet.
J.
9,
150-154.
O'Reilly,
R.
A.,
Aggler,
P.
M.
and
Leang,
L.
S.
(1963).
Studies
on
coumarin
anticoagulant
drugs:
pharmacodynamics
of
warfarin
in
man.
.1.
din.
Invest.
42,
1542-1551.
Reeks,
H.
C.
(1952).
Diseases
of
the
horse's
foot.
Chicago,
Alex
Agar.
Wintzer,
H.
J.
(1964).
Navicular
diseases:
a
clinical,
pathological
and
radiographic
study.
Dissertation,
Utrecht.
Youatt,
Mr.
(1836).
The
Veterinarian
8,
485.
RÉSUMÉ
Vingt
chevaux
atteints
de
maladie
naviculaire
ont
ete
traite
a
l'aide
de
warfarin,
administre
oralement.
Le
dosage
utilise
visait
a
prolonger
de
2
a
4
secondes
le
temps
d'action
de
la
prothrombine.
Le
dosage
initiale-
ment
adopte
fut
de
0.018
mg/kg,
et
les
doses
furent
accrues
de
20
%
par
paliers,
jusqu'a
obtention
de
l'effet
desire.
Les
doses
finales
varierent
de
0.012
mg/kg
a
0.75
mg/kg.
Tous
les
animaux
traites
recurent
du
warfarin
chaque
jour.
Dix
sept
animaux
furent
apparem-
ment
gueris
et
les
trois
autres
montrerent
une
amelior-
ation
fonctionnelle
appreciable.
La
moyenne
d'age
des
chevaux
etait
de
7
ans
1/2,
la
duree
moyenne
de
la
boiterie
etait
de
neuf
mois
et
le
temps
moyen
pour
obtenir
la
guerison
fut
de
sept
semaines
a
compter
du
debut
du
traitement.
ZUSAMMENFASSUNG
Zwanzig
strahlbeinlahme
Pferde
wurden
mit
oral
gegebenem
Warfarin
behandelt.
Die
Dosis
war
wirkungsabhangig
und
sollte
eine
Verlangerung
der
Prothrombinzeit
um
2
bis
4
Sekunden
hervorrufen.
Initial
wurden
0.018
mg/kg
Korpergewicht
gegeben
und
anschliessend
wurde
die
Dosis
urn
je
zwanzig
Prozent
verandert,
bis
der
gewiinschte
Effekt
erreicht
war.
Die
Enddosis
variierte
von
0.012
mg/kg
bis
0.75
mg/kg.
Alle
behandelten
Falle
erhielten
wahrend
des
ganzen
Versuchs
taglich
Warfarin.
17
Tiere
gingen
nachher
gerade
und
die
verbleibenden
3
zeigten
eine
deutliche
Verbesserung
ihrer
Gange.
Das
Durchschnittsalter
der
Pferde
betrug
7.5
Jahre,
die
durchschnittliche
Dauer
der
Lahmheit
9
Monate
und
die
durchschnittliche
Abheilungsdauer
nach
Therapiebeginn
7
Wochen.
Accepted
for
publication
13.2.79
ABSTRACT
Respiratory
System
and
Diseases
The
role
of
allergy
in
chronic
pulmonary
disease
of
horses
HALLIWELL,
R.
E.
W.,
FLEISCHMAN,
J.
B.,
MACKAY-SMITH,
M.,
BEECH,
J.
and
GUNSON,
D.
E.
(1979).
J.
Am.
vet.
med.
Ass.
174
(3),
277-
281.
Twenty-five
normal
horses
and
25
suffering
from
chronic
pulmonary
disease
(CPD)
were
challenged
with
intradermal
injections
of
allergens
which
included
those
from
fungal
spores,
feed
and
barn
dust.
These
allergen
sites
were
compared
with
control
sites
at
half,
4
and
48
hours
after
injection.
Although
all
the
normal
horses
had
positive
reactions
to
1
or
more
allergens,
the
authors
found
a
significantly
greater
incidence
of
positive
reactions
at
half
an
hour
and
4
hours
in
horses
suffering
from
CPD.
Delayed
reactions
(ie,
48
hours)
were
rarely
encountered
in
either
group.
Skin
biopsies
were
collected
from
test
sites
in
8
horses
and
histological
examination
revealed
typical
allergic
reactions
(Types
I,
III
and
IV).
The
authors
suggest
the
study
has
confirmed
that
allergy
plays
a
major
role
in
the
aetiology
of
CPD.
Furthermore,
encouraging
results
have
been
achieved
from
hyposensitisation
of
12
horses
suffering
from
the
disease
and
which
had
predominantly
immediate-type
reactions.
T.
R.
C.
GREET