AHA Project: ANTIOXIDANT SUPPLEMENTATION
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Anonymous
1999
RCT
N overall:
11,324
Secondary
prevention
Primary study outcome(s):
Death, nonfatal MI, and
stroke
None reported
N women:
1,665
Status post
MI
1) N-3 polyunsaturated fatty
acid (PUFA) 1 gm
QD + placebo
(n = 2,836)
GISSIPrevenzione
Trial
Mean age:
59.4
Age range:
SD 10.6%
% Diabetics:
14.8
% Caucasian:
NR
2) Vitamin E 300
mg QD + placebo
(n = 2,830)
3) N-3 PUFA and
Vitamin E
(n = 2,830)
4) Placebo +
placebo
(n = 2,828)
Clinical endpoints of interest:
1) Composite outcome(s):
2-way analysis:
Vitamin E: 730
Placebo: 770
RR 0.95 (95% CI, 0.86-1.05)
4-way analysis:
Vit E: 371
Placebo: 414
RR 0.89 (0.77-1.03)
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
2-way analysis:
Vit E: 83
Placebo: 95
RR 0.87 (0.65-1.17)
4-way analysis:
Vit E: 39
Placebo: 41
RR 0.95 (0.61-1.47)
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
2-way analysis:
Vit E: 488
1 of 25
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
None reported
Mean f/u 4.3 yrs
Placebo: 529
RR 0.92 (0.82-1.04)
4-way analysis:
Vit E: 252
Placebo: 293
RR 0.86 (0.72-1.02)
6) CHF:
NR
7) PVD:
NR
Arad
2005
RCT
N overall:
1,005
Primary
prevention
1) Treatment
(n=490)
N women:
Treatment 27%
Control
26%
Men and
women with
coronary
calcium
scores at or
above the
80th
percentile for
age and
gender.
Atorvastatin
20 mg QD
Mean age:
59 +-6
Age range:
50-70
% Diabetics:
Treatment
9
Control
8
% Caucasian
NR
All study
participants
received ASA
81 mg QD
Primary study outcome(s):
Progression of coronary
calcification and prevention
of atheroschlerotic
cardiovascular disease
events
Vitamin C
1 gm QD
Vitamin E
(alpha-tocopherol)
1000 U QD
2) placebo
(n=515)
Clinical endpoints of interest:
1) Composite outcome(s):
Coronary death, non-fatal
MI, coronary revasculization
procedures, nonhemorrhagic stroke, and
peripheral revascularization
procedure
1)Treatment 34/490 (6.9%)
2) Control 51/515 (9.9%)
p= 0.07
2) Heart attack/MI:
1)Treatment
9/490 (1.8%)
2) Control
17/515 (3.3%)
p=0.14
3) Stroke (e.g. hemorrhagic,
non-hemorrhagic, TIA, fatal
2 of 25
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
or nonfatal):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Boaz
2000
RCT
N overall:
196
Secondary
prevention
N women:
61
Hemodialysis
patients with
preexisting
cardiovascular
disease
Mean age:
64
Age range:
40-75
% Diabetics:
43
% Caucasian:
NR
1) Vitamin E 800
IU/day
(n = 97)
2) Placebo
(n = 99)
Primary study outcome(s):
Composite of MI, stroke,
peripheral vascular disease,
unstable angina
Clinical endpoints of interest:
1) Composite outcome(s):
Vitamin E n = 18
Placebo n = 34
RR 0.54 (95% CI, 0.33-0.89)
p = 0.016
2) Heart attack/MI:
Vitamin E n = 8
Placebo n = 18
RR 0.45 (0.20-0.99)
p = 0.04
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
Vitamin E n = 5
Placebo n = 6
RR 0.85 (0.30-2.70)
p = NS
4) Revascularization
3 of 25
None reported
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
Not applicable (no women.)
There was no
evidence for any
association
between
vegetable intake
and total CHD
events.
procedure (PCI, bypass):
NR
5) Death/mortality:
Vitamin E n = 31
Placebo n = 29
RR = 1.09 (0.70-1.70)
p = NS
6) CHF:
NR
7) PVD:
Vitamin E n = 3
Placebo n = 6
RR 0.39 (0.11-1.43)
p = NS
Dauchet
2004
PRIME
study
Cohort
study
N overall:
5,982 France
2,105 Northern
Ireland
(total 8,087)
N women:
0
Mean age:
NR
Age range:
50-59
% Diabetics:
NR
% Caucasian
NR
Primary
prevention
Men free of
CHD
Fruit and vegetable
intake was
assessed by a
food-frequency
questionnaire and
frequency of
consumption was
divided into tertiles.
Adjustment was
made for education
level, smoking,
physical activity,
alcohol
consumption ,
employment status,
BMI, blood
pressure, and
serum total and
HDL cholesterol.
Freq/d
All vegetables
I) < or = 0.79
II) 1-1.29
Primary study outcome(s):
Incident cases of acute
coronary events over a 5-yr
f/u
Clinical endpoints of interest:
1) Composite outcome(s):
249 ischemic events
All vegetables
I) RR= 1 (reference)
II) RR= 0.84 (0.63, 1.13)
III) RR= 1.01 (0.88, 1.15)
p for trend= 0.93
Citrus fruit
I) RR= 1 (reference)
II) RR= 0.77 (0.56, 1.05)
III) RR= 0.76 (0.56, 1.04)
p for trend= 0.14
Other fruit
I) RR=1 (reference)
II) RR= 0.98 ( 0.68, 1.39)
4 of 25
Frequency of
citrus fruit, but
not other fruit,
intake is
associated with
lower rates of
acute coronary
evens.
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
III) > or = 1.5
III) RR= 0.96 (0.71, 1.30)
p for trend= 0.58
Citrus fruit
I) < or= 0.07
II) 0.14-0.29
III) > or = .5
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
1) Composite outcome(s):
Major vascular event:
Vitamin n = 402
Placebo n = 415
RR not specified, 95% CI
spans 1.0 in figure
Simvastatin
numbers not
reported in this
manuscript
2) Heart attack/MI:
NR
3) Stroke (e.g. hemorrhagic,
non-hemorrhagic, TIA, fatal
or nonfatal):
NR
Other fruit
I) < or = 0.57
II) 0.64-1.14
III) > or = 1.29
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Heart
Protection
Study
Collaborative
Group
2002
RCT
N overall:
20,536
N women:
5,082
Mean age:
NR
Age range:
40-80
% Diabetics:
19
% Caucasian:
NR
Mixed
Subjects with
CAD, PVD,
or DM,
f/u 5 yrs
1) Vitamin E 600
mg, Vitamin C 250
mg, and Beta
carotene 20 mg
QD, plus
simvastatin or
placebo
(n = 10,269)
Primary study outcome(s):
Major coronary events
2) Placebo
vitamins, plus
simvastatin or
placebo
(n = 10,267)
Age stratified outcomes:
Vitamins
<65: 945/4,919
≥65 <70: 617/2,473
≥ 70: 744/2,877
Clinical endpoints of interest:
1) Composite outcome(s):
Vitamins n = 2,306
Placebo n = 2,312
RR 1.00 (95% CI, 0.94-1.06)
Placebo
<65: 977/4,920
≥65 <70: 560/2,418
5 of 25
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
≥ 70: 755/2,929
2) Heart attack/MI:
Vitamins n = 1,063
Placebo n = 1,047
RR 1.02 (0.94-1.11)
Subgroup Analyses of
Clinical Endpoints in
Women
5) Death/mortality:
NR
Notes
6) CHF:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
Vitamins n = 511
Placebo n = 518
RR 0.99 (0.87-1.12)
4) Revascularization
procedure (PCI, bypass):
Coronary
Vitamins n = 623
Placebo n = 615
RR 0.98 (0.90-1.06)
All revascularizations
(including peripheral),
Vitamin n = 1,058
Placebo n = 1,086
5) Death/mortality:
Vitamins n = 1,446
Placebo n = 1,389
RR 1.04 (0.97-1.12)
6) CHF:
NR
7) PVD:
Vitamins n = 1,954
Placebo n = 2,028
RR = NS
KlipsteinGrobusc
h
1999
Cohort
study
N overall:
4,802
Primary
prevention
N women:
Subjects free
Questionnaire of
diet and
supplement intake
Primary study outcome(s):
MI (fatal and nonfatal)
Clinical endpoints of interest:
6 of 25
None reported
Multivariate
adjusted RR
(adjusted for
age, sex, BMI,
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
2,946
of MI at
baseline,
given
questionnaire
about diet
and
supplement
intake,
f/u 4 yrs
1) Beta carotene
intake
1) Composite outcome(s):
See heart attack/MI
2) Vitamin E intake
2) Heart attack/MI:
Beta carotene:
Highest tertile of intake n =
30
Lowest tertile n = 53
RR 0.55 (95% CI, 0.34-0.83)
Mean age:
67
Age range:
55-95
% Diabetics:
8.0-10.2
% Caucasian:
NR
3) Vitamin C intake
N’s per tertile:
1st (lowest) n =
1,601
2nd n = 1,601
3rd n = 1,600
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
pack/yrs,
income,
education,
alcohol, and
other
supplements)
Vitamin E:
Highest tertile n = 42
Lowest tertile n = 33
RR = 1.21 (0.75-1.98)
Vitamin C
Highest tertile n = 36
Lowest tertile n = 47
RR = 1.05 (0.65-1.67)
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Kushi
1996
Cohort
study
N overall:
34,486
Primary
prevention
N women:
34,486
Post menopausal
Questionnaire
regarding diet and
use of
supplements,
followed with every
Primary study outcome(s):
Death from CHD
Clinical endpoints of interest:
1) Composite outcome(s):
7 of 25
See under “Outcomes” (all
women)
All RRs
multivariate
adjusted
Study
Design
No. of Patients
Mean age:
61
Age range:
55-69
% Diabetics:
NR
% Caucasian:
NR
Patient
Population
Interventions
Outcomes
women
other year
questionnaires
a) Total Vitamin E: Highest
quintile (n = 51) compared
with lowest quintile (n = 52),
RR = 0.96 (0.62-1.51)
N of quintiles
NR
b) Vitamin E from
supplements: Highest
quintile (n = 21) compared
with lowest quintile (n =
162), RR = 1.09 (0.67-1.77)
c) Vitamin C total: Highest
quintile (n = 61) compared
with lowest quintile (n = 44),
RR = 1.49 (0.96-2.30)
d) Vitamin C from
supplements: Highest
quintile (n = 8) compared
with lowest quintile (n =
141), RR = 0.74 (0.30-1.83)
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
8 of 25
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Lee
2004
Cohort
study
N overall:
836
Mixed
Diet was assessed
with a foodfrequency
questionnaire at
baseline, and
subjects were
followed for 15
years.
Primary study outcome(s):
Relation between vitamin C
intake and mortality from
total cardiovascular disease,
coronary artery disease, and
stroke.
Iowa
Women's
Health
Study
N women:
836
Mean age:
62.4
Age range:
55-69
% Diabetics:
100
% Caucasian
99
Postmenopausal
diabetic
women free
of CAD
Adjusted relative
risks of coronary
artery disease
mortality were
calculated across
quintiles of total
vitamin C intake
from food and
supplements.
Adjustment was for
cardiovascular
disease risk
factors, type of
diabetes
medication used,
duration of
diabetes, and
intakes of folate,
vitamin E, and
beta-carotene.
Clinical endpoints of interest:
1) Composite outcome(s):
NR
2) Heart attack/MI:
NR
3) Stroke (e.g. hemorrhagic,
non-hemorrhagic, TIA, fatal
or nonfatal):
I) RR= 1.0 (reference)
II) RR= 0.52 (0.16-1.66)
III) RR= 1.23 (0.44-3.40)
IV) RR= 2.22 (0.82-6.01)
V) RR= 2.57 (0.86-7.66)
p for trend = 0.02
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality: 281
cardiac deaths
Quintile of median vitamin C
intake from food and
supplements (mg/d)
I) RR= 1.0 (reference)
II) RR= 0.97 (0.63, 1.49)
III) RR= 1.11 ( 0.71, 1.72)
IV) RR= 1.47 (0.93, 2.32)
V) RR= 1.84 ( 1.12, 3.01)
p for trend < 0.01
6) CHF:
NR
9 of 25
Subgroup Analyses of
Clinical Endpoints in
Women
See under “Outcomes” (all
women)
Notes
Only
supplemental
vitamin C
showed a
positive
association with
mortality
endpoints.
A high vitamin C
intake from
supplements is
associated with
an increased
risk of
cardiovascular
disease
mortality in
postmenopausal
women with
diabetes.
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
1) Composite outcome(s):
Effect on primary outcome
shown in figure, confidence
intervals cross 1.0
Substudy of
HOPE trial for
diabetics
7) PVD:
NR
Lonn
2002
RCT
N overall:
3,654
N women:
1,358
Mean age:
65.4
Age range:
SD 6.5
% Diabetics:
100
% Caucasian:
NR
Mixed
Documented
CVD (69%)
or diabetes
plus one
other risk
factor
1) Vitamin E 400 IU
QD with either
ramipril 10 mg QD
or placebo
(n = 1,838)
2) Placebo Vitamin
E with either
ramipril 10 mg QD
or placebo
(n = 1,816)
Primary study outcome(s):
Composite of nonfatal MI,
stroke, CV death
Clinical endpoints of interest:
1) Composite outcome(s):
Vit E n = 325
Placebo n = 313
RR 1.03 (95% CI, 0.88-1.21)
p = 0.70
2) Heart attack/MI:
Vit E n = 212
Placebo n = 209
RR 1.01 (0.83-1.22)
p = 0.96
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
Vit E n = 103
Placebo n = 84
RR 1.21 (0.91-1.62)
p = 0.20
4) Revascularization
procedure (PCI, bypass):
Vit E n = 279
Placebo n = 278
RR 0.99 (0.66-1.25)
p = 0.95
5) Death/mortality:
Vit E n = 218
Placebo n = 232
RR 0.93 (0.77-1.12)
p = 0.44
6) CHF:
10 of 25
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
None reported
RRs are ageand sexadjusted
Vit E n = 241
Placebo n = 201
RR 1.21 (1.00-1.46)
p = 0.05
7) PVD:
NR
Losonczy
1996
Cohort
study
N overall:
11,178
N women:
7,524
Mean age:
75-78
Age range:
67-105
% Diabetics:
9.2-17.1
% Caucasian:
77.6-96.7
Mixed
Questionnaire
about medication
and use of
supplements
Numbers of users
as follows:
Vit E users
(n = 320)
Vit E & C users
(n = 184)
Vit E alone
(n = 136)
Vit C alone
(n = 418)
Primary study outcome(s):
Mortality
Clinical endpoints of interest:
1) Composite outcome(s):
NR
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
CV mortality
a) Vitamin E users n = 19,
RR 0.53 (95% CI, 0.34-0.84)
b) Vitamin E & C users n =
10 RR 0.47 (0.25-0.87)
c) Vitamin E alone n = 9
RR 0.64 (0.33-1.24)
d) Vitamin C alone n = 46
RR 1.00 (0.74-1.34)
All-cause mortality:
a) All Vitamin E users n = 76
RR 0.66(0.53-0.83)
b) Vitamin E & C users n =
40 RR 0.58(0.42-0.79)
11 of 25
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
c) Vitamin E alone n = 36
RR 0.80 (0.57-1.11)
d) Vitamin C alone n = 154
RR 1.04 (0.89-1.23)
6) CHF:
NR
7) PVD:
NR
Marchioli
2001
RCT
N overall:
9,658
Secondary
prevention
N women:
1,665
Recent (<3
mos) MI
Mean age:
59
Age range:
SD 11
% Diabetics:
15
% Caucasian:
NR
1) N-3 Polyunsaturated fatty
acid (PUFA) 850822 mg QD
(n = 2,835)
2) Vitamin E 300
mg QD
(n = 2,830)
3) N-3 PUFA and
Vitamin E
(n = 2,830)
4) Control
(n = 2,828)
Primary study outcome(s):
See composite endpoint
Clinical endpoints of interest:
1) Composite outcome(s):
Death, nonfatal MI, and
nonfatal stroke:
a) N-3 PUFA n = 358, RR
0.84 (95% CI, 0.73-0.97)
b) Vitamin E n = 376, RR
0.89 (0.78-1.03)
c) N-3 PUFA + Vitamin E n =
360, RR 0.85 (0.74-0.98)
d) Control n = 419
2) Heart attack/MI:
a) N-3 PUFA n = 198, RR
0.78 (0.65-0.94)
b) Vitamin E n = 224, RR
0.89 (0.74-1.06)
c) N-3 PUFA + Vitamin E n =
220, RR 0.87 (0.73-1.04)
d) Control n = 251
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
a) N-3 PUFA n = 50, RR
1.24 (0.82-1.87)
b) Vitamin E n = 37, RR 0.92
(0.59-1.44)
c) N-3 PUFA + Vitamin E n =
12 of 25
None reported
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
See under “Outcomes” (all
women)
F/u 16 yrs
220, RR 0.87 (0.73-1.04)
d) Control n = 251
4) Revascularization
procedure (PCI, bypass):
a) N-3 PUFA n = 588, RR
1.01 (0.90-1.14)
b) Vitamin E n = 538, RR
0.93 (0.82-1.04)
c) N-3 PUFA + Vitamin E n =
584, RR 1.02 (0.90-1.14)
d) Control n = 575
5) Death/mortality:
a) N-3 PUFA n = 239, RR
0.79 (0.67-0.94)
b) Vitamin E n = 255, RR
0.85(0.72-1.00)
c) N-3 PUFA + Vitamin E, n
= 238, RR 0.79 (0.67-0.94)
d) Control n = 299
6) CHF:
NR
Osganian
2005
Prospe
ctive
Cohort
study
N overall:
85,118
N women:
85,118
Mean age:
46-48
Age range:
30-55
% Diabetics:
2
% Caucasian
NR
Mixed
Food-frequency
questionnaire
assessed
consumption of
vitamin C and other
nutrients.
I) ≤93 mg/day
II) 94-132 mg/day
III) 133-183 mg/day
IV) 184-359 mg/day
V) ≥ 360 mg/day
Users of
supplements
(n=68,666)
Primary study outcome(s):
Incident cases of coronary
heart disease (nonfatal MI
and fatal CHD)
Clinical endpoints of interest:
1) Composite outcome(s):
1,356 incident cases of
CHD.
Quntile of vitamin C intake
(multivariate plus total
Vitamin E and carotene
intake, with supplements)
I) reference
II) RR= 0.87 (0.73- 1.05)
III) RR= 0.94 (0.77-1.15)
13 of 25
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
No supplements
(n=16,186)
IV) RR= 0.98 (0.79-1.22)
V) RR= 0.73 (0.57-0.94)
p for trend = 0.005
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
Not applicable (no women)
No effect of
supplements on
progression of
angina (without
hard end points)
Dietary (without
supplements)
I) reference
II) RR= 0.91 (0.68-1.22)
III) RR= 0.86 (0.62-1.18)
IV) RR= 0.84 (0.60-1.18)
V) RR= 0.86 (0.59-1.26)
p for trend = 0.52
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Rapola
1998
RCT
N overall:
29,133
1) Alpha tocopherol
50 mg QD
(n = 460)
Primary study outcome(s):
Self-reported recurrence of
angina
2) Alpha tocopherol
+ beta carotene
(n = 456)
Clinical endpoints of interest:
1) Composite outcome(s):
NR
Age range:
50-69
3) Beta carotene 20
mg QD
(n = 420)
% Diabetics:
5-8
4) Placebo
(n = 459)
2) Heart attack/MI:
a) Vit E n = 81
RR 0.95 (95% CI, 0.68-1.33)
b) Vit E + beta carotene n =
74, RR 0.86 (0.61-1.20)
c) Beta carotene n = 79
RR 1.08 (0.78 to 1.50)
d) Placebo n = 80, RR 1.00
N women:
0
Mean age:
58.8
% Caucasian:
Mixed
Smokers with
angina
pectoris
14 of 25
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
Not applicable (no women)
All RRs
multivariate
adjusted
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Rapola
1997
RCT
N overall:
1,862
Secondary
prevention
N women:
0
Smokers with
previous MI
Mean age:
59-60
Median f/u
5.3 yrs
1) Alpha tocopherol
50 mg QD
(n = 466)
2) Beta carotene 20
mg QD
(n = 461)
Age range:
55-64
3) Alpha tocopherol
plus beta carotene
(n = 497)
% Diabetics:
6-9
4) Placebo
(n = 438)
% Caucasian:
NR
Primary study outcome(s):
First major coronary event
Clinical endpoints of interest:
1) Composite outcome(s):
Alpha tocopherol n = 94, RR
0.90 (0.67-1.22)
Alpha tocopherol and beta
carotene n = 123, RR 1.14
(0.87-1.51)
Beta carotene n = 113, RR
1.11 (0.84-1.48)
Placebo n = 94, RR 1.00
2) Heart attack/MI:
Alpha tocopherol n = 64,
RR 0.81 (0.56-1.17)
Alpha tocopherol and beta
carotene n = 86, RR 1.14
(0.82-1.59)
Beta carotene n = 79, RR
1.11(0.79-1.56)
Placebo n = 66, RR = 1.00
15 of 25
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Rimm
1993
Cohort
study
N overall:
39,910
N women:
0
Mean age:
NR
Age range:
40-75
% Diabetics:
0
% Caucasian:
NR
Primary
prevention
Questionnaire
administered every
other year about
dietary habits and
vitamin
supplements over 4
yrs
N’s per quintile
NR
Primary study outcome(s):
Coronary disease (fatal,
nonfatal MI, CABG, PCI)
Clinical endpoints of interest:
1) Composite outcome(s):
Highest quintile Vitamin E
intake (n = 115 CHD cases)
compared with lowest
quintile (n = 155):
Multivariate RR 0.64 (0.490.83), p = 0.003
Subjects with  10 years
supplement use had RR
0.65 (0.46-0.92) compared
to nonusers, p = 0.10
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
16 of 25
Not applicable (no women)
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Stampfer
1993
Cohort
study
N overall:
87,245
N women:
87,245
Mean age:
NR
Age range:
34-59
% Diabetics:
NR
% Caucasian:
NR
Primary
prevention
Vitamin E
consumption as
reported by dietary
and supplement
intake on
questionnaire every
2 yrs
N’s per quintile
NR
Primary study outcome(s):
Major coronary disease
Clinical endpoints of interest:
1) Composite outcome(s):
MI, death from CVD:
a) Highest quintile of Vit E
intake (diet and
supplement), RR = 0.66
(95% CI, 0.50-0.87)
b) Highest quintile of Vit E
intake (diet only), RR = 0.95
(0.72-1.23)
c) Vit E users
(supplements), RR = 0.54
(0.36-0.82) compared with
nonusers
a) and b) are adjusted for
age and smoking and
compared with lowest
quintile of Vit E intake
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
17 of 25
See under “Outcomes” (all
women)
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
None reported
Did not appear
to adjust for
medications
(although had
beta blocker vs.
no beta blocker
in final analysis)
non-hemorrhagic, TIA):
Vit E users RR = 0.71 (0.391.31) compared with
nonusers
4) Revascularization
procedure (PCI, bypass):
Vit E users RR = 0.73 (0.481.09) compared with
nonusers
5) Death/mortality:
Vit E users RR = 0.87 (0.691.10) compared with non
users
6) CHF:
NR
7) PVD:
NR
Stephens
1996
RCT
N overall:
2,002
Secondary
prevention
N women:
312
Known CAD
(90% had
angina)
Mean age:
61.8
Age range:
SD 9
% Diabetics:
Treated: 9.9
Placebo: 7
% Caucasian:
NR
1) Alpha
tocopherol
400 IU (n = 489) or
800 IU (n = 546)
daily
2) Placebo
(n = 967)
Primary study outcome(s):
Nonfatal MI, composite of
nonfatal MI plus death
Clinical endpoints of interest:
1) Composite outcome(s):
Nonfatal MI plus death
Treated: 50
Placebo: 67
2) Heart attack/MI:
Treated: 14
Placebo: 41
p = 0.0001
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
Treated: 1
placebo: 1
18 of 25
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
Treated: 36
Placebo: 26
6) CHF:
NR
7) Major adverse cardiac
event:
Treated: 41
Placebo: 62
(p = 0.015)
Tornwall
2004
ATBC
study,
post-trial
effects
RCT
N overall:
29,133
N women:
0
Mean age:
NR
Age range:
50-69
% Diabetics:
NR
% Caucasian
NR
Mixed
Male
smokers
1) Vitamin E,
alpha-tocopherol
50 mg
(n=5,794)
Primary study outcome(s):
Major coronary event (MCE)
defined as nonfatal MI, CHD
death
2) beta-carotene 20
mg
(n=5,768)
Clinical endpoints of interest:
1) Composite outcome(s):
Risk for MCE (n=2059) was
0.95 (95% CI 0.87-1.04) for
Vit E recipients compared
with non-recipients, and
1.14 (1.04-1.24) among beta
carotene recipients
compared with nonrecipients
3) both
supplements
(n=5,741)
4) placebo
(n=5,841)
Daily for 5-8 yrs
In trial results
Placebo: 1.0 (reference)
Vit E only: 0.98 (0.87-1.11)
Both: 0.97 (0.86-1.10)
Beta-carotene: 1.03 (0.921.17)
p=0.75
Post-trial results
19 of 25
Not applicable (no women)
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Placebo: 1.0 (reference)
Vit E only: 0.94 (0.83-1.07)
Both: 1.08 (0.95-1.22)
Beta-carotene: 1.13 (1.001.28)
p=0.02
2) Heart attack/MI:
NR
3) Stroke (e.g. hemorrhagic,
non-hemorrhagic, TIA, fatal
or nonfatal):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
Fatal CHD n=1066
Alpha tocopherol 0.94 (0.831.06)
Beta carotene 1.11 (0.991.25)
6) CHF:
NR
7) PVD:
NR
Virtamo
1998
RCT
N overall:
27,271
Primary
prevention
N women:
0
Finnish male
smokers age
50-69
Mean age:
57
Age range:
1) Vitamin E 50 mg
QD
(n = 6,820)
2) Beta carotene 20
mg QD
(n = 6,821)
3) Beta carotene
plus Vitamin E
Primary study outcome(s):
First major coronary event
Clinical endpoints of interest:
1) Composite outcome(s):
Nonfatal MI or CV death:
Vit E n = 519, RR 0.98 (95%
CI, 0.87-1.10)
Beta carotene n = 547
(RR 1.03, 0.91-1.16)
20 of 25
Not applicable (no women)
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
50-69
(n = 6,781)
% Diabetics:
3.7-4.3
4) Placebo
(n = 6,849)
Combo: n = 511
(RR 0.97,0.86-1.09)
Placebo n = 534, RR 1.0
% Caucasian:
NR
Duration: 5-8 yrs
Subgroup Analyses of
Clinical Endpoints in
Women
2) Heart attack/MI:
NR
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
NR
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
NR
6) CHF:
NR
7) PVD:
NR
Waters
2002
RCT
N overall:
423
N women:
423
Mean age:
65
Age range:
SD 9
% Diabetics:
36
% Caucasian:
66
Mixed
Postmenopausal
women with
at least one
15-75%
lesion
(43% with
prior MI)
1) Estrogen 6.25
mg/progesterone
2.5 mg QD, plus
Vitamin E 400 IU
and Vitamin C 500
mg QD
(n = 107)
2) Estrogen 6.25
mg/progesterone
2.5 mg QD, plus
placebo
(n = 103)
3) Placebo HRT,
plus Vitamin E 400
IU and Vitamin C
500 mg QD
Primary study outcome(s):
Annualized mean change in
lumen diameter
Clinical endpoints of interest:
1) Composite outcome(s):
Death/nonfatal MI/stroke:
Placebo/placebo: 5
HRT/placebo: 11
Placebo/Vit E and C: 10
HRT/Vit E and C: 15
p = 0.12
2) Heart attack/MI:
Placebo/placebo: 1
HRT/placebo: 3
Placebo/Vit E and C: 3
HRT/Vit E and C: 1
21 of 25
See under “Outcomes” (all
women)
Notes
Study
Design
No. of Patients
Patient
Population
Interventions
Outcomes
(n = 105)
p = 0.56
4) Placebo HRT
and placebo
Vitamins
(n = 108)
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
Placebo/placebo: 3
HRT/placebo: 4
Placebo/Vit E and C: 1
HRT/Vit E and C: 5
p = 0.41
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
None reported
Vitamin E had
no significant
effect either on
patients
receiving
ramipril or on
patients
receiving
placebo
4) Revascularization
procedure (PCI, bypass):
Placebo/placebo: 28
HRT/placebo: 13
Placebo/Vit E and C: 19
HRT/Vit E and C: 21
p = 0.1
5) Death/mortality:
Placebo/placebo: 2
HRT/placebo: 4
Placebo/Vit E and C: 6
HRT/Vit E and C: 10
p = 0.08
6) CHF:
NR
7) PVD:
NR
Yusuf
2000
HOPE
Study
RCT
N overall:
9,541
N women:
2,545
Mean age:
66
Age range:
SD 7
Mixed
Established
CAD or DM
plus another
risk factor
1) Vitamin E 400
IU QD plus ramipril
10 mg QD or
placebo
(n = 4,761)
2) Placebo plus
either ramipril or
placebo
(n = 4,780)
Primary study outcome(s):
Composite of MI, stroke, CV
death
Clinical endpoints of interest:
1) Composite outcome(s):
MI, stroke, CV death:
Vit E: 772
Placebo: 739
RR 1.05 (95% CI, 0.95-1.16)
22 of 25
Study
Design
No. of Patients
% Diabetics:
38
% Caucasian:
NR
Patient
Population
Interventions
Outcomes
Subgroup Analyses of
Clinical Endpoints in
Women
Notes
2) Heart attack/MI:
Vit E: 532
Placebo: 524
RR 1.02 (0.90-1.15)
3) Stroke (hemorrhagic,
non-hemorrhagic, TIA):
Vit E: 209
Placebo: 180
RR 1.17 (0.95-1.42)
4) Revascularization
procedure (PCI, bypass):
NR
5) Death/mortality:
Vit E: 535
Placebo: 537
RR 1.00 (0.89-1.13)
6) CHF:
Vit E: 530
Placebo: 457
RR 1.17 (1.03-1.32)
7) PVD: claudication
Vit E: 762
Placebo 753
RR 1.02 (0.92-1.13)
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