ORIGINAL
ARTICLE
Vitamin
E
in
angina
pectoris
T.
W.
Anderson,
b.m.,
b.ch.,
ph.d.,
Toronto
Summary:
The
claim
that
the
symptoms
of
angina
pectoris
can
usually
be
relieved
by
large
doses
of
vitamin
E
has
been
reinvestigated
by
means
of
a
randomized
double-blind
trial.
The
trial
lasted
nine
weeks
and
consisted
of
two
parts.
One
part
was
conducted
as
a
regular
double-blind
trial
involving
40
patients,
half
of
whom
received
3200
IU
of
vitamin
E
daily,
while
an
equal
number
received
an
indistinguishable
placebo.
The
second
part
of
the
trial
involved
15
patients
who
were
already
taking
a
regular
daily
dose
of
between
400
and
2400
IU
of
vitamin
E.
Eight
patients
were
assigned
the
same
(or
a
larger)
dose
of
vitamin
E,
while
seven
received
placebo.
Neither
part
of
the
trial
yielded
statistically
convincing
evidence
that
vitamin
E
is
of
value
in
the
treatment
of
angina,
but
a
small
beneficial
effect
could
not
be
ruled
out.
Taken
in
conjunction
with
the
positive
(but
statistically
non-significant)
results
obtained
in
the
only
other
double-blind
trial
of
vitamin
E
ever
carried
out
on
angina,
and
the
encouraging
results
reported
by
other
investigators
in
the
treatment
of
intermittent
claudication,
it
is
suggested
that
further
double-blind
trials
are
justified.
Resume:
La
vitamine
E
dans
I'angine
de
poitrine
Nous
avons
reevalue
le
bien-fonde
de
I'affirmation
que
de
fortes
doses
de
vitamine
E
peuvent
generalement
soulager
les
symptdmes
de
I'angine
de
poitrine
et
avons,
a
cet
effet,
utilise
la
methode
a
double
insu,
les
malades
etant
pris
au
hasard.
Ces
essais
ont
dure
neuf
semaines
et
ont
ete
divises
en
deux
parties.
La
premiere
partie,
faite
suivant
les
regles
classiques
de
la
methode
a
double
insu,
portaient
sur
40
malades,
dont
la
moitie
recevaient
3200
UI
de
vitamine
E
par
jour,
et
un
nombre
6gal
de
malades
un
placebo
qu'on
ne
peut
distinguer.
La
seconde
partie portait
sur
15
malades
qui
prenaient
deja
regulierement
une
dose
quotidienne
de
vitamine
E
variant
de
40
a
2400
UI.
Huit
de
ces
malades
ont
continue
de
prendre
leur
dose
habituelle
de
vitamine
E
(voire
une
dose
plus
forte),
tandis
que
les
sept
autres
recevaient
un
placebo.
Ni
la
premiere
serie
d'essais,
ni
la
seconde
n'ont
fourni
de
preuve
convaincante,
sur
le
plan
statistique,
que
la
vitamine
E
a
une
valeur
therapeutique
dans
I'angine
de
poitrine,
bien
qu'il
soit
impossible
d'eliminer
completement
la
Reprint
requests
to:
Dr.
T.
W.
Anderson,
Dept.
of
Epidemiology
and
Biometrics,
School
of
Hygiene,
University
of
Toronto,
Toronto,
Ont.
M5S
1A1
possibilite
d'un
leger
effet
favorable.
Si
on
compare
ces
resultats
aux
resultats
positifs
(bien
que
negligeables
au
point
de
vue
statistique)
qui
ont
ete
obtenus
dans
la
seule
autre
etude
a
double
insu
de
la
vitamine
E
sur
I'angine
qui
ait
jamais
ete
publiee,
et
si
on
les
rapproche
des
resultats
encourageants
rapportes
par
d'autres
chercheurs
dans
le
traitement
de
la
claudication
intermittente,
il
semble
bien
que
d'autres
essais
du
genre
seraient
justifies.
The
tocopherols
are
a
group
of
substances
that
are
widely
distributed
in
nature
and
whose
main
function
appears
to
be
that
of
protecting
unsaturated
fatty
acids
(particularly
the
polyunsaturates)
from
oxidation,
a
property
demon-
strable
both
in
vitro
and
in
vivo.
Of
the
eight
known
toco¬
pherols,
the
alpha
form
is
the
most
powerful
in
its
anti-
oxidant
action,
and
has
been
designated
vitamin
E.
Deficiency
causes
illness
and
death
in
a
wide
range
of
animal
species,
owing
to
the
formation
of
highly
reactive
lipid
peroxides
that
seriously
disrupt
the
metabolism
of
a
variety
of
tissues,
including
the
myocardium.
It
is
there¬
fore
theoretically
possible
that
a
deficiency
of
the
anti-
oxidant
tocopherols
could
lead
to
myocardial
damage
in
man,
and
that
an
adequate
intake
of
vitamin
E
(currently
thought
to
be
of
the
order
of
20
to
30
mg
per
day)
might
help
to
protect
the
human
myocardium.
However,
most
of
the
controversy
that
has
existed
for
the
past
quarter
of
a
century
over
the
place
of
vitamin
E
in
cardiovascular
disease
has
been
concerned
not
so
much
with
the
possible
importance
of
an
adequate
dietary
intake
of
this
vitamin
as
over
its
use
in
large
doses
as
a
therapeutic
agent.
The
first
claim
that
angina
pectoris
could
be
relieved
by
massive
doses
of
vitamin
E
appeared
in
a
letter
to
Nature
in
June
1946,
in
which
Vogelsang
and
Shute
re¬
ported
that
they
had
found
that
vitamin
E
in
a
dose
range
of
200
to
600
mg
per
day
would
dramatically
diminish
or
abolish
anginal
pain.1
In
the
following
year
Shute,
Shute
and
Vogelsang
supported
this
claim
with
84
case
histories
of
angina
patients
in
90%
of
whom
improvement
had
occurred
after
an
average
of
seven
weeks
on
vitamin
E
therapy.2*3
Between
1947
and
1950
a
number
of
negative
reports
were
published,413
but
like
the
original
positive
report,
most
were
based
on
uncontrolled
clinical
observations.
Only
three
controlled
studies
were
reported,
and
only
that
by
Rinzler
et
al9
was
double-blind
(Table
I).
Since
1950
there
have
been
no
published
reports
of
further
trials,
although
some
physicians
have
continued
to
claim
dramatic
success
CMA
JOURNAL/FEBRUARY
16,
1974/VOL.
110
401
in
the
treatment
of
angina
and
other
diseases,
and
have
criticized
the
early
negative
trials
on
the
grounds
of
ina¬
dequate
design,
dosage
and
duration.314"19
These
conflicting
claims
have
been
widely
publicized
in
the
last
few
years,
and
the
medical
profession
has
been
accused
of
rejecting
vitamin
E
without
a
fair
trial.1719'21*22
Unfortunately,
it
is
notoriously
difficult
to
evaluate
anti-
angfria
drugs.
Not
only
is
angina
almost
entirely
subjective
in
nature,
but
anxiety
often
plays
a
major
role
in
the
symp¬
tomatology.
It
follows
that
any
substance,
however
inert,
will
appear
to
be
effective
provided
it
is
prescribed
with
enough
enthusiasm
by
a
physician
in
whom
the
patient
has
confidence.
The
problem
in
evaluating
the
dramatic
claims
made
for
vitamin
E
is
therefore
not
to
establish
whether
the
claims
are
exaggerated
(they
are
almost
bound
to
be),
but
whether
beneath
the
placebo
effect
is
a
small
but
useful
therapeutic
effect.
None
of
the
early
controlled
trials
involved
large
enough
numbers
of
subjects
to
demonstrate
convincingly
the
pres¬
ence
or
absence
of
an
effect
of small
magnitude.
However,
the
results
of
the
double-blind
trial
by
Rinzler
were
com¬
patible
with
a
small
positive
effect
(Table
II),
and
it
was
hoped
that
in
the
present
study
it
would
be
possible
to
recruit
large
enough
numbers
to
establish
whether
this
was
a
real
effect
or
a
statistical
artefact.
(Unfortunately,
as
will
be
seen,
only
a
modest
number
of
subjects
could
be
recruited.)
In
the
opinion
of
Dr.
E.
V.
Shute,
the
failure
of
the
Rinzler
trial
to
demonstrate
a
statistically
significant
effect
of
vitamin
E
was
due
to
the
use
of
an
inadequate
dose.19
In
the
present
trial
a
much
higher
dose
(3200
IU
per
day)
was
therefore
proposed,
and
at
this
dosage
level
Drs.
E.
V.
and
W.
E.
Shute
believed
that
a
trial
of
nine
weeks'
duration
would
be
adequate
to
demonstrate
a
large
effect,
of
the
order
of
80%
improvement.23
Initially
it
was
hoped
that
it
would
be
possible
to
quan-
titate
the
change
(if
any)
in
the
anginal
status
of
some
patients
by
means
of
exercise
testing.
This
did
not
prove
possible,
so
that
apart
from
nitroglycerin
consumption
the
assessments
in
this
study
were
purely
qualitative.
Contrary
to
some
widely
held
opinions,
however,
this
need
not
invalidate
a
trial
of
antiangina
therapy.
Since
the
object
of
treatment
is
to
reduce
symptoms
and
increase
the
patient's
ability
to
lead
a
normal
life,
these
are
the
criteria
on
which
assessment
of
treatment
should
be
based.
The
fact
that
they
are
subjective
criteria
should
be
no
obstacle
to
valid
group
comparisons,
provided
that
the
subjective
bias
is
the
same
in
both
groups,
i.e.
that
the
trial
is
truly
double-blind.20
(As
normally
carried
out,
exercise
testing
also
has
a
large
subjective
component:
the
patient
is
taken
through
increasing
levels
of
exercise
until
he
or
she
can
do
no
more,
either
because
of
pain
or
because
of
inadequate
motivation.)
In
the
present
trial,
changes
in
angina
status
were
therefore
judged
on
the
basis
of
the
attending
physician's
clinical
impression,
changes
in
nitroglycerin
consumption,
and
changes
in
the
patient's
daily
record
of
severity
of
pain
and
amount
of
activity.
Method
A
letter
was
submitted
to
this
journal24
inviting
the
cooperation
of
interested
physicians,
and
a
similar
invita-
tion
was
circulated
to
a
number
of
cardiologists
in
the
Toronto
area.
Physicians
who
responded
were
sent
a
de¬
tailed
description
of
the
proposed
trial,
together
with
an
explanatory
letter
and
consent
form
for
their
patients.
Both
documents
had
previously
been
approved
by
the
University
of
Toronto
committee
on
human
experiments.
Patients
were
informed
that
half
of
them
would
receive
placebo,
and
that
they
were
free
to
withdraw
from
the
trial
at
any
time
if
they
so
desired.
Physicians
were
asked
to
recruit
patients
whose
angina
was
reasonably
stable,
who
had
had
no
major
change
in
health
status
(such
as
an
acute
myocardial
infarction)
or
usual
medications
for
at
least
three
months,
and
who
could
be
depended
on
to
take
their
test
capsules
regularly
and
keep
adequate
records.
In
view
of
some
of
the
reported
side
effects
of
large
doses
of
vitamin
E16
physicians
were
asked
not
to
recruit
patients
who
were
on
the
brink
of
congestive
failure,
or
who
had
any
evidence
of
rheumatic
heart
disease.
Since
the
object
was
to
assess
the
effect
of
one
variable
(vitamin
E)
while
all
others
remained
con¬
stant,
patients
remained
on
their
other
usual
medications
throughout
the
trial.
Physicians
who
were
already
prescribing
vitamin
E
for
their
angina
patients
were
invited
to
enrol
these
patients
in
a
separate
trial
in
which
the
effect
of
diiscontinuing
the
vitamin
E
could
be
assessed.
Dr.
W.
E.
Shute
has
claimed
that
such
patients
have
a
recurrence
of
symptoms,
often
after
only
a
few
days
without
their
vitamin
E.16
Patients
were
paired
as
closely
as
possibly
by
sex
and
age,
then
assigned
a
code
number
from
a
computer-
generated
list
of
paired
random
numbers
that
had
pre¬
viously
been
used
to
number
the
vitamin
and
placebo
bottles.
After
the
code
list
had
been
used
to
number
the
bottles,
it
was
given
to
a
colleague
for
safe-keeping
until
after
all
the
records
had
been
returned
and
initial
tabula¬
tions
carried
out.
Each
patient
then
received
a
numbered
bottle
containing
enough
capsules
for
the
nine-week
trial,
together
with
a
list
of
instructions
and
11
record
cards,
two
for
a
pre¬
liminary
baseline
period
and
nine
for
the
trial
itself.
(Sub¬
sequently,
it
was
necessary
to
use
the
first
two
weeks
of
the
trial
as
the
baseline
period
since
very
few
of
the
preliminary
two
cards
were
sent
in.)
Table
I.Some
of
the
major
negative
reports
on
the
efficacy
of
vitamin
E
in
angina
pectoris
?Where
a
range
of
doses
was
used,
a
weighted
mean
has
been
calculated;
1
mg
of
vitamin
E
is
approximately
equal
to
one
international
unit.
fSame
patients
on
other
medications
or
placebo;
single-blind.
JMatched
controls;
double-blind.
Table
II.Results
of
the
double-blind
trial
by
Rinzler
et
al
in
1950,
using
approximately
300
mg
of
vitamin
E
daily
for
an
average
of
16
weeks
Vitamin
Placebo
Improved
No
change
Worse
5
10
0
Total
15
14
402
CMA
JOURNAL/FEBRUARY
16,
1974/VOL.
110
The
placebo
If
a
double-blind
trial
is
to
have
any
validity,
the
placebo
must
be
truly
indistinguishable
from
the
active
preparation,
short
of
chemical
analysis.
This
may
be
very
difficult
to
achieve,
particularly
if
(as
in
this
case)
the
active
prepara¬
tion
can
easily
be
obtained
from
any
drug
store
and
used
as
a
basis
of
comparison
by
the
inquisitive
patient
or
physician.
The
form
of
vitamin
E
used
in
this
study
was
the
succinate,
available
in
capsules
as
a
dry
powder
of
creamy
colour,
with
a
slightly
nutty
flavour
and
slightly
granular
texture.
This
powder
proved
to
be
very
difficult
to
imitate,
and
after
several
unsuccessful
attempts
to
modify
the
colour
and
texture
of
the
placebo
powder
(lactose)
to
suit,
it
was
decided
to
colour
both
preparations
bright
yellow
and
to
have
a
small
amount
of
crystalline
sucrose
added
to
each.
This
appeared
to
obscure
effectively
the
colour,
taste
and
texture
of
the
original
material,
and
this
was
verified
by
having
23
colleagues
examine
the
capsules
and
their
contents,
using
the
commercially
available
preparation
as
a
standard
of
reference.
Fourteen
were
unable
to
identify
the
experimental
vitamin
capsule,
five
identified
it
cor¬
rectly,
and
four
incorrectly
picked
the
placebo
capsule.
The
potency
of
the
vitamin
capsules
were
subsequently
confirmed
by
analysis
at
the
laboratories
of
the
health
protection
branch,
Health
&
Welfare
Canada.
Physicians'
records
When
enrolling
a
patient
in
the
trial
the
attending
physi¬
cian
was
asked
to
fill
in
a
basic
record
sheet
that
provided
information
on
the
patient's
age,
sex,
duration
of
angina,
ete.
To
reduce
the
possibility
of
undesirable
side
effects
passing
unnoticed
during
the
course
of
the
trial,
the
physician
was
asked
to
record
resting
pulse
and
blood
pressure
each
week
and
to
enquire
after
any
change
in
the
patient's
general
health.
Between
visits
patients
were
advised
to
temporarily
discontinue
their
capsules
and
contact
their
physician
if
any
unusual
symptoms
appeared.
At
the
end
of
the
trial
the
attending
physician
was
asked
to
record
his
overall
assessment
of
the
patient's
health
during
the
trial,
and
particularly
whether
the
patient's
angina
had
improved
or
worsened.
Table
lll.Characteristics
of
vitamin
and
placebo
groups
in
the
regular
and
discontinuation
trials
Regular
Discontinuation
Total
subjects
Sex:
Male
Female
Age:
Mean
Range
18(20)
11(13)
7
18(20)
11(13)
7
58.4(57.7)
63.6(63.2)
41-74
43-78
Duration
of
angina
(years):
Mean
6.0(5.8)
Range
1-13
Nitroglycerin
consumption*
Mean
20.4(22.8)
0-180
Blood
pressure
(mm
Hg):
Systolic,
Mean
138(136)
Range
104-190
5.2(5.1)
5/12-25
11.0(10.4)
0-71
135(135)
110-190
8
4
4
57.3
48-63
4.0
2-7
9.2
0-30
143
124-150
Diastolic,
Mean
Range
91(89)
60-110
82(82)
83
60-100
80-90
7
4
3
64.0
52-75
4.4
1-11
11.2
0-40
139
130-150
81
80-90
Figures
in
parentheses
include
the
four
patients
who
were
possible
non-reactors.
*Per
week,
based
on
first
two
weeks.
Patient's
records
A
set
of
weekly
record
cards
was
supplied
to
each
patient.
These
were
ordinary
thin
white
cards
measuring
4x6
inches.
One
side
was
marked
off
into
seven
columns,
headed
Sunday
through
Saturday,
and
eight
horizontal
rows.
The
first
two
rows
were
for
recording
on
each
day
the
number
of
"vitamin"
capsules
taken
and
the
number
of
nitroglycerin
tablets
used.
The
next
three
rows
were
headed
"Angimal
pain"
and
the
patient
was
asked
to
put
a
check
mark
in
one
of
the
rows
marked
"worse
than
usual",
"same
as
usual",
or
"better
than
usual".
The
last
three
rows
were
headed
"Activity",
and
the
patient
was
asked
to
put
a
check
mark
against
"able
to
do
less
than
usual",
"able
to
do
same
as
usual",
or
"able
to
do
more
than
usual".
At
the
top
of
each
card
was
a
space
for
the
patient's
name,
the
attending
physician's
name,
the
date,
and
a
brief
set
of
instructions,
including
the
suggestion
that
the
back
of
the
card
be
used
to
record
unusual
symptoms
or
other
comments.
To
assist
in
the
analysis
of the
pain
and
activity
records,
a
weekly
net
score
was
calculated
for
each
patient,
assign-
ing
a
value
of
1
to
each
day
on
which
pain
was
"worse
than
usual",
0
for
each
day
"same
as
usual",
and
+1
for
each
day
"better
than
usual".
Similarly,
the
information
on
activity
was
coded
as
.1
(less),
0
(same),
or
+
(more
than
usual).
The
weekly
score
for
either
pain
or
activity
could
thus
range
between
a
high
of
+7
and
a
low
of
.7.
Subjects
The
19
collaborating
physicians
(9
family
physicians
and
10
cardiologists)
were
able
to
enrol
a
total
of
68
patients,
48
for
the
"regular"
trial
and
20
for
the
"discontinuation"
trial.
Regular
trial
Of
the
48
patients
initially
enrolled
in
the
regular
trial,
seven
patients
(V3,
P4)
were
later
withdrawn
for
the
fol¬
lowing
reasons:
One
patient
(P)
was
admitted
to
hospital
for
coronary
artery
surgery,
one
(P)
suffered
a
myocardial
infarction
in
the
first
week,
one
(V)
suffered
a
stroke
in
the
third
week,
and
two
(IV,
1P)
lost
interest
and
failed
to
take
their
capsules
or
keep
records.
The
other
two
patients
were
withdrawn
from
the
trial
after
a
few
days
because
of
suspected
side
effects.
One
(V)
complained
of
diarrhea;
one
(P)
complained
of
severe
heartburn.
(These
two
patients
are
included
in
the
later
discussion
of
side
effects.)
In
addition,
one
patient
stopped
taking
his
cap¬
sules
after
only
five
weeks
because
of
an
influenza-like
illness.
His
physician
considered
that
this
illness
was
in¬
fectious
in
nature
and
was
unrelated
to
the
capsules
he
was
taking.
There
thus
remained
40
patients,
33
of
whom
completed
nine
full
weeks
of
records.
In
five
cases
(3V,
2P)
only
eight
weeks
of
records
could
be
used
because
one
record
card
was
incomplete
or
missing,
in
one
(V)
only
seven
weeks
of
records
were
available,
and
one
other
patient
(V)
withdrew
from
the
study
after
seven
weeks
because
of
persistent
diarrhea.
Ten
patients
had
at
some
time
tried
vitamin
E
on
their
own
initiative.
In
six
the
dosage
used
had
been
relatively
small
or
the
period
of
ingestion
relatively
short,
but
in
the
other
four
the
dosage
and
duration
had
been
great
enough
to
raise
the
possibility
that
these
patients
had
already
demonstrated
themselves
to
be
"non-reactors".
In
most
of
the
subsequent
analysis
their
results
have
therefore
been
expressed
separately
from
those
of
the
other
36
patients.
Some
of
the
basic
characteristics
of
the
patients
involved
in
the
regular
trial
are
summarized
in
Table
III.
As
might
be
expected,
in
view
of
the
pairing
procedure
used,
the
CMA
JOURNAL/FEBRUARY
16,
1974/VOL.
110
403
age
and
sex
distribution
were
reasonably
similar
in
the
two
groups,
but
the
average
nitroglycerin
consumption
in
the
vitamin
group
was
considerably
higher
than
in
the
placebo
group.
The
first
recorded
blood
pressure
readings
also
tended
to
be
somewhat
higher
in
the
vitamin
group.
In
the
majority
of
patients
the
diagnosis
of
angina
was
purely
clinical,
based
on
a
history
of
exercise-induced
chest
pain
promptly
relieved
by
nitroglycerin
or
rest.
In
most
cases
there
was
also
evidence
of
a
closely
related
disorder
such
as
myocardial
infarction,
cerebrovascular
ischemia,
or
peripheral
vascular
disease.
Eight
patients
(4V,
4P)
had had
coronary
angiograms
done,
all
of
which
showed
severe
narrowing
of
the
coronary
arteries.
Two
patients
(both
on
placebo)
had
undergone
surgical
treat¬
ment
for
their
angina;
one
had had
a
Vineberg
procedure
in
1970,
the
other
a
bypass
operation
early
in
1972.
Thirty-one
patients
(16V,
15P)
had
at
some
time
suf¬
fered
a
recognized
myocardial
infarction.
In
25
cases
(13V,
12P)
the
angina
had
appeared
following
the
infarction,
while
in
the
other
six
cases
it
had
developed
some
time
before
the
first
recognized
infarction.
Two
patients
(IV,
1P)
had
previously
experienced
transient
ischemic
attacks,
and
another
(P)
had
previously
suffered
a
mild
stroke.
Three
patients
(all
in
the
vitamin
group)
suffered
from
peripheral
vascular
disease.
Seven
patients
(3V,
4P)
were
being
treated
for
hypertension,
three
(2V,
1P)
were
mildly
diabetic,
two
(IV,
1P)
had
chronic
obstructive
lung
disease,
and
there
was
one
case
(V)
of
hyperuricemia.
In
addition
to
nitroglycerin,
patients
were
receiving
the
following
drugs:
propranolol
(8V,
12P),
long-acting
nitrates
(IV,
8P),
diuretic
or
antihypertensive
drugs
(5V,
6P),
digitalis
compounds
(6V,
2P)
and
diazepam
(2V,
4P).
Eight
patients
were
cigarette
smokers
(4V,
4P),
two
smoked
cigars
(IV,
1P),
two
smoked
a
pipe
(IV,
1P),
and
28
were
non-smokers
(14V,
14P).
Twenty-three
patients
(9V,
14P)
were
under
the
care
of
a
family
physician;
17
(11V,
6P)
were
under
the
care
of
a
cardiologist.
Discontinuation
trial
Initial
enrolment
was
20
patients,
but
four
were
with¬
drawn
by
their
attending
physician
because
of
unreliability
(mainly
failure
to
keep
records),
and
one
decided
not
to
take
part
in
the
trial
because
of
persistent
dizziness
and
nausea
that
developed
a
few
days
before
she
was
due
to
begin
taking
the
test
capsules.
Of
the
15
patients
that
remained,
eight
continued
to
receive
a
dose
of
vitamin
E
that
was
as
large
or
larger
Table
IV.Final
assessment
by
attending
physicians
of
change
in
angina
symptoms
in
patients
in
vitamin
and
placebo
groups
by
the
end
of
the
regular
trial
Vitamin
Placebo
Much
improved
Improved
Slightly
improved
No
change
Slightly
worse
Total
18(20)
18(20)
Figures
in
parentheses
include
the
four
patients
who
were
possible
non-reactors.
Table
V.Final
assessment
by
attending
physicians
of
change
in
angina
symptoms
in
patients
in
vitamin
and
placebo
groups
by
the
end
of
the
discontinuation
trial
than
their
regular
dose,
while
the
seven
patients
on
placebo
had
their
daily
dose
reduced
to
nil
from
400
(2
patients),
800
(1),
1200
(3),
or
2400
(1)
IU.
The
basic
characteristics
of
the
patients
in
the
discon¬
tinuation
trial
are
also
summarized
in
Table
III.
Results
Regular
trial
According
to
the
final
assessment
by
attending
physicians,
the
majority
of
patients
in
each
group
experienced
no
change
in
their
angina,
while
the
remainder
experienced
changes
that
ranged
from
"much
improved"
to
"slightly
worse".
There
was
no
striking
difference
betwen
the
two
groups,
although
the
distribution
was
slightly
more
favour-
able
to
the
vitamin
group
(Table
IV).
Inclusion
of
the
four
possible
non-reactors
improved
the
record
of
the
placebo
group,
but
had
no
effect
on
the
vitamin
group,
thus
virtually
eliminating
the
difference
between
the
two
groups.
Nitroglycerin
consumption
was
higher
in
the
vitamin
group
from
the
start,
and
the
mean
weekly
intake
rose
from
18.7
in
the
first
week
to
23.5
in
the
last
week
(Fig.
1).
In
the
placebo
patients
the
corresponding
figures
were
10.9
and
6.4.
Interpretation
of
these
changes
was
made
difficult
by
the
fact
that
they
were
due
largely
to
one
or
two
patients
in
each
group
who
had
a
large
initial
intake
and
showed
great
variation
(Fig.
2).
One
patient
in
the
vitamin
group
(responsible
for
the
high
positive
value
in
Fig.
2)
had
an
+1
-I
i_i_i_
12345678
9
WEEKS
FIG.
1.Weekly
means
of
nitroglycerin
consumption,
pain
and
activity
scores,
in
the
regular
trial
(excluding
the
four
possible
non-reactors).
404
CMA
JOURNAL/FEBRUARY
16,
1974/VOL.
110
average
weekly
consumption
of
180
nitroglycerin
tablets
.
more
than
the
entire
placebo
group
combined.
Most
of
the
patients
in
each
group
showed
little
change
in
nitro¬
glycerin
consumption
during
the
trial.
(Note:
Where
the
full
nine
weeks
of
records
were
not
available,
those
of
the
last
two
weeks
for
that
individual
were
used
to
calculate
the
differences
shown
in
Fig.
2.
Similarly,
the
weekly
averages
in
Fig.
1
were
based
on
those
patients
completing
the
full
week's
records.)
Most
of
the
patients
also
showed
little
change
in
pain
or
activity
scores
at
the
end
of
the
trial
compared
to
the
beginning
(Figs.
1
and
2).
The
change
in
activity
scores
was
more
favourable
to
the
vitamin
group,
but
the
dif¬
ference
between
the
groups
was
not
statistically
significant.
Discontinuation
trial
Of
the
seven
patients
who
had
previously
been
on
a
regular
daily
dose
of
vitamin
E
and
received
placebo
cap¬
sules
during
the
study
period,
three
dropped
out
because
their
angina
became
worse
(Table
V).
One
patient
dropped
out
after
one
week,
one
after
six
weeks
(complaining
of
an
increase
in
intermittent
claudication
as
well
as
in
angina),
and
one
after
seven
weeks.
These
patients
had
previously
been
on
a
daily
dose
of
2400
IU
(for
one
year),
400
IU
(for
two
months),
and
1200
IU
(for
two
years).
A
fourth
patient
stayed
on
the
placebo
capsules
for
the
full
nine
weeks,
but
complained
that
her
angina
had
been
worse,
particularly
during
the
final
three
weeks.
She
had
previously
been
on
a
dose
of
400
IU
daily
for
18
months.
The
other
three
patients
in
the
placebo
group
were
un¬
changed
after
nine
weeks.
Two
of
these
patients
had
pre¬
viously
been
on
1200
IU
daily
for
two
years,
the
third
on
800
IU
for
four
months.
Of
the
eight
patients
who
continued
to
receive
vitamin
E
six
completed
the
full
nine
weeks,
one
ran
out
of
cap¬
sules
in
the
last
week,
and
one
stopped
taking
the
capsules
after
six
weeks
because
of
intestinal
cramps
(this
patient
had
previously
been
on
a
daily
dose
of
400
IU
of
vitamin
E,
and
was
on
3200
IU
during
the
trial).
None
of
these
patients
complained
of
increased
angina.
The
difference
in
the
experience
of
the
two
groups
approached
statistical
significance
(P<0.1
by
a
standard
two-tailed
test).
Other
findings
Electrocardiograms
taken
at
the
beginning
and
the
end
of
the
trial
period
were
available
for
16
patients
(7V,
9P)
in
the
regular
trial.
These
cardiograms
were
read
"blind"
by
two
of
the
cardiologists
in
the
study.
A
change
was
reported
in
only
one
case
in
which
there
was
a
suggestion
of
increased
ischemia
in
lead
V5.
This
patient
was
on
placebo
and
was
the
one
patient
whose
angina
was
con¬
sidered
(by
another
physician)
to
have
worsened
during
the
trial
(Table
V).
Blood
pressure
readings
at
least
seven
weeks
apart
were
available
for
33
patients
(15V,
18P)
in
the
regular
trial.
The
mean
systolic
pressure
fell
from
140
to
137
mm
Hg
in
the
vitamin
subjects,
and
from
139
to
138
mm
Hg
in
the
placebo
subjects.
Corresponding
mean
values
for
diastolic
pressures
were:
vitamin
85
and
75,
and
placebo
81
and
82.
Side
effects
Information
on
possible
side
effects
was
obtained
from
the
attending
physicians
and
directly
from
the
patients
in
the
form
of
comments
on
the
back
of
the
record
cards.
In
the
earlier
trials
listed
in
Table
I
a
number
of
symp¬
toms
had
been
noted
in
patients
while
they
were
taking
vitamin
E.
These
included
headache
(five
patients),5,6
giddi-
ness
(two),5,6
flushing
of
the
face
(one),6
and
slight
con¬
stipation
(one).5
In
the
present
trial,
in
spite
of
dosages
that
were
approximately
10
times
as
great,
none
of
the
foregoing
symptoms
was
encountered
among
the
patients
taking
vitamin
E;
headache
and
constipation
were
reported
by
two
patients
who
proved
to
have
been
on
placebo.
The
only
other
possible
side
effects
reported
by
the
68
patients
(including
drop-outs)
who
began
the
trial
were:
nausea
(IV,
2P),
heartburn
(2P),
diarrhea
(3V),
intestinal
cramps
(IV),
and
tiredness
and
itching
(1P).
Of
the
three
patients
in
the
vitamin
group
who
suffered
from
diarrhea,
two
found
it
very
troublesome
and
withdrew
from
the
trial
on
account
of
it,
but
in
the
third
it
was
mild
and
she
completed
the
full
nine
weeks.
The
patient
who
complained
of
intestinal
cramps
was
in
the
discontinuation
trial
and
his
dose
had
been
increased
from
400
to
3200
IU
daily.
He
reported
that
the
cramps
disappeared
when
he
discontinued
his
capsules,
but
returned
as
soon
as
he
+
100
+
50f
-50
-100
\-
NITR0GLYCER1N
r
It0
o
o
+
20
h
+
10
.10
h
-20
h
ACTIVITY
SCORE
o
oo
xg
o
.oooooo-
oo
o
FIG.
2.Individual
changes
in
nitroglycerin
consumption,
pain
and
activity
scores
between
the
first
and
last
two
weeks
of
the
regular
trial.
(The
four
possible
non-reactors
are
each
represented
by
an
x.)
CMA
JOURNAL/FEBRUARY
16,
1974/VOL.
110
405
started
taking
them
again.
He
therefore
withdrew
from
the
trial
afted
six
weeks
and
returned
to
his
regular
dose
of
vitamin
E.
Therefore
the
only
symptoms
that
appeared
to
be
re-
lated
to
the
ingestion
of
these
large
doses
of
vitamin
E
were
related
to
the
lower
gastrointestinal
tract,
namely
cramps
and
diarrhea.
Discussion
The
results
of
the
regular
trial
provide
little
support
for
the
claim
that
80
to
90%
of
angina
patients
experience
relatively
prompt
relief
of
symptoms
from
a
large
daily
intake
of
vitamin
E.
On
the
other
hand,
the
number
of
subjects
was
too
small
to
enable
a
firm
conclusion
to
be
reached
concerning
the
possible
existence
of
a
less
dramatic
effect.
Similarly,
although
it
is
intriguing
that
in
the
discon-
tinuation
study
four
out
of
seven
patients
on
placebo
experienced
a
recurrence
of
symptoms
(compared
to
none
of
the
eight
on
vitamin),
these
numbers
are
very
small
and
the
difference
could
well
be
a
statistical
artefact.
Furthermore,
it
should
be
recognized
that
these
patients
may
not
have
been
as
"blind"
as
those
in
the
regular
trial:
it
is
conceivable
that
in
patients
who
have
grown
used
to
a
large
daily
intake
of
vitamin
E,
the
disappearance
of
some
slight
side
effect
(such
as
increased
intestinal
ac-
tivity?)
might
subconsciously
alert
them
to
the
fact
that
they
have
been
switched
to
a
placebo.
(It
is,
of
course,
also
possible
that
the
reverse
effect
could
have
occurred
in
the
regular
trial,
but
it
is
less
likely.)
However,
there
is
an
alternative
explanation
for
the
apparent
success
of
the
discontinuation
trial
and
the
ap-
parent
failure
of
the
regular
trial,
namely
that
vitamin
E
is
effective
in
some
cases,
but
that
duration
is
more
critical
than
dose.
Three
of
the
four
patients
who
relapsed
in
the
discontinuation
trial
had
previously
been
on
vitamin
E
for
at
least
one
year
at
dosage
levels
of
400,
1200
and
2400
IU.
Longer
duration
of
treatment
might
also
explain
why
the
results
of
the
previous
double-blind
trial9
were
more
favourable
than
the
results
of
the
present
regular
trial,
since
Rinzler's
patients
were
studied
for
periods
of
10
to
20
weeks,
compared
with
only
nine
weeks
in
the
present
trial.
Studies
of
vitamin
E
treatment
in
a
related
disease
-
intermittent
claudication
-
also
suggest
that
duration
may
be
a
critical
factor.25.27
The
recent
work
of
Haeger
is
of
particular
interest
in
this
regard,
since
he
has
found
that
while
subjective
improvement
usually
takes
at
least
three
months
to
appear
(on
300
IU
daily),
improved
vascular
flow
cannot
be
demonstrated
until
after
about
12
months
of
treatment.
Furthermore,
he
has
observed
that
when
the
vitamin
E
therapy
is
discontinued
there
is
approximately
a
one-month
delay
before
symptoms
reappear.28
This
time
interval
is
rather
similar
to
the
six-
or
seven-week
interval
seen
in
three
of
the
four
patients
who
relapsed
in
the
present
discontinuation
study.
There
would
appear
to
be
enough
doubt
about
the
efficacy
of
vitamin
E
in
angina
to
justify
a
further
double-
blind
trial
in
which
patients
would
be
followed
for
a
longer
period
of
time,
and
(if
a
large
enough
number
of
subjects
could
be
assembled)
the
effect
of
two
or
three
dosage
levels
determined.
1
am
hopeful
that
such
a
trial
can
be
started
within
the
next
few
months.
Meanwhile
it
must
be
emphasized
that
the
usefulness
of
vitamin
E
in
angina
pectoris
remains
unproved.
As
pointed
out
in
the
introduction,
uncontrolled
clinical
ob-
servations
almost
inevitably
result
in
overoptimistic
claims,
but
as
Marks
has
so
aptly
put
it:
"Vitamin
E
has,
un-
fortunately,
suffered
general
discredit
owing
to
the
wide
claims
that
have
been
made
which
could
not
be
corro-
borated.
Such
wide
claims,
however,
should
not
prejudice
the
case
of
tocopherol
in
defined
indications
where
there
is
adequate
evidence
of
activity".29
I
thank
the
following
physicians
for
their
assistance
in
carrying
out
this
investigation:
W.
V.
Basser,
B.
Boadway,
T.
R.
H.
Box,
C.
G.
Cameron,
B.
Charles,
A.
W.
Chisholm,
D.
F.
Docherty,
H.
D.
Hall,
G.
L.
Magee,
P.
G.
Morse,
M.
M.
Nedilski,
J.
W.
Neville,
P.
Newbigging,
F.
Rosen,
L.
Schwartz,
A.
J.
L.
Solway,
K.
H.
Staroste,
C.
J.
Wallace
and
J.
K.
Wilson.
I
also
thank
Professor
D.
B.
W.
Reid
for
his
very
helpful
advice;
Drs.
W.
E.
and
E.
V.
Shute
and
J.
H.
Barker
for
their
assistance
in
planning
the
trial;
Mr.
W.
J.
Gutterson
of
Webber
Pharmaceuticals
for
supplying
the
vitamin
and
placebo
capsules;
and
Dr.
J.
N.
Thompson,
health
protection
branch,
Department
of
National
Health
and
Welfare,
Canada,
for
arranging
an
independent
analysis
to
confirm
the
potency
of
the
vitamin
capsules.
References
1.
VOGELSANG
A,
SHUTE
EV:
Effect
of
vitamin
E
in
coronary
heart
disease.
Nature
157:
772
1946
2.
SHUTE
WE,
SHUTE
EV,
V'OGELSANG
A:
Vitamin
E
in
heart
disease:
the
anginal
syndrome.
Med
Rec
160:
91,
1947
3.
Idem:
Vitamin
E
in
angina
pectoris.
Lancet
1:
301,
1948
4.
BALL
KP:
Vitamin
E
in
angina
pectoris.
Ibid,
p
116
5.
LEVY
H,
BoAs
EP:
Vitamin
E
in
heart
disease.
Ann
Intern
Med
28:
1117,
1948
6.
MAKINSON
DH,
OLEESKY
S,
STONE
RV:
Vitamin
E
in
angina
pec-
toris.
Lancet
1:
102,
1948
7.
DONEGAN
CK,
MESSER
AL,
ORGAIN
ES,
et
al:
Negative
results
of
tocopherol
therapy
in
cardiovascular
disease.
Am
J
Med
Sc
217:
294,
1949
8.
RAVIN
IS,
KATZ
KH:
Vitamin
E
in
the
treatment
of
angina
pectoris.
N
Engi
J
Med
240:
331,
1949
9.
RINZLER
SH,
BAKST
H,
BENJAMIN
ZH,
et
al:
Failure
of
alpha
tocopherol
to
influence
chest
pain
in
patients
with
heart
disease.
Circulation
1:
288,
1950
10.
BAERS
S,
HEINE
WI,
GELFOND
DB:
The
use
of
vitamin
E
in
heart
disease.
Am
J
Med
Sci
215:
542,
1948
11.
EICHERT
H:
Vitamin
E,
a
therapeutic
perpetration.
South
Med
J
42:
717,
1949
12.
EISEN
ME,
GROSS
H:
Vitamin
E
in
arteriosclerotic
heart
and
peri-
pheral
vascular
disease.
NY
State
J
Med
49:
2422,
1949
13.
RUSH
HP:
Experience
with
vitamin
E
in
coronary
disease.
Calif
Med
71:
391,
1949
14.
SHUTE
EV,
VOGELSANG
AB,
SKELTON
FR,
et
al:
The
influence
of
vitamin
E
on
vascular
disease.
Surg
Gynecol
Obstet
86:
2,
1948
15.
VOGELSANG
A,
SHUTE
WE,
SHUTE
EV:
Vitamin
E.
Can
Med
Assoc
J
59:
585,
1948
16.
SHUTE
WE,
SHUTE
EV:
Alpha
tocopherol
in
cardiovascular
disease.
London,
Shute
Foundation,
1954
17.
SHUTE
WE,
TAUB
HJ:
Vitamin
E
for
ailing
and
healthy
hearts.
New
York,
Pyramid
Bks,
1969
18.
VOGELSANG
A:
Twenty-four
years
using
alpha-tocopherol
in
degenera-
tive
cardiovascular
disease.
Angiology
21:
275,
1970
19.
SHUTE
EV:
in
BAILEY
H:
Vitamin
E,
Your
Key
to
a
Healthy
Heart.
New
York,
Arc
Bks,
1968
20.
ANDERSON
TW,
REID
DBW,
BEATON
GH:
Vitamin
C
and
the
common
cold:
a
double-blind
trial.
Can
Med
Assoc
J
107:
503,
1972
21.
LEGGE
RF:
Will
your
heart
kill
you?
Executive:
April,
1971
22.
Idem:
Resolving
the
vitamin
E
controversy.
Can
Res
Dev:
September/October,
1971
23.
SHUTE
EV,
SHUTE
WE:
Personal
communication
24.
ANDERSON
TW:
Study
of
vitamin
E
therapy
proposed.
Can
Med
Assoc
J
106:
538,
1972
25.
BOYD
AM,
MARKS
J:
Treatment
of
intermittent
claudication:
a
reappraisal
of
the
value
of
alpha-tocopherol.
Angiology
14:
198,
1963
26.
HAEGER
K:
The
treatment
of
peripheral
occlusive
arterial
disease
with
alpha-tocopherol
as
compared
with
vasodilator
agents
and
antiprothrombin
(dicumarol).
Vasc
Dis
5:
199,
1968
27.
WILLIAMs
HTG,
FENNA
D,
MACBETH
RA:
Alpha-tocopherol
in
the
treatment
of
intermittent
claudication.
Surg
Gynecol
Obstet
132:
662,
1971
28.
HAEGER
K:
Personal
communication,
1973
29.
MARKS
J:
Critical
appraisal
of
the
therapeutic
value
of
alpha-toco-
pherol.
Vitam
Horm
20:
573,
1962
406
CMA
JOURNAL/FEBRUARY
16,
1974/VOL.
110
