© 1997 American Heart Association, Inc.
Articles |
Effect of 
-Tocopherol (Vitamin E) and ß-Carotene Supplementation on the Incidence of Intermittent Claudication in Male Smokers
From the National Public Health Institute, Helsinki, Finland (M.E.T., J.V., J.K. Haukka, A.A., J.K. Huttunen), and the National Cancer Institute, Bethesda, Md (D.A., B.K.E.).
Correspondence to Dr Markareetta Törnwall, ATBC Study, Department of Nutrition, National Public Health Institute, Mannerheimintie 166, 00300 Helsinki, Finland. E-mail markareetta.tornwall{at}ktl.fi
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Abstract |
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Abstract We examined the primary preventive effect of vitamin E (
-tocopherol) and ß-carotene supplementation on
intermittent claudication. The subjects—participants in the
Alpha-Tocopherol, Beta-Carotene Cancer Prevention
Study—were male smokers aged 50 to 69 years who were randomly assigned
to receive 50 mg of -tocopherol daily, 20 mg of
ß-carotene daily, both, or placebo. At baseline, there were 26 289
men with no history or symptoms of intermittent claudication. The Rose
questionnaire on intermittent claudication was administered annually to
discover incident cases. We observed 2704 cases of first occurrence of
typical intermittent claudication during a median follow-up time of 4.0
years. Compared with placebo, the adjusted relative risk for typical
intermittent claudication among those who received
-tocopherol only was 1.11 (95% confidence interval,
1.00-1.24); among those who received -tocopherol and
ß-carotene, 1.02 (0.91-1.13); and among those who received
ß-carotene only, 1.02 (0.92-1.14). When we compared the
-tocopherol–supplemented subjects with those who
received no -tocopherol, the adjusted relative risk for
typical intermittent claudication was 1.05 (0.98-1.14), and for
ß-carotene–supplemented subjects compared with those who did not
receive ß-carotene, the relative risk was 0.96 (0.89-1.04). In
conclusion, no primary preventive effect on intermittent claudication
was observed among middle-aged male smokers who were supplemented with
-tocopherol, ß-carotene, or both.
Key Words: intermittent claudication • prevention • vitamin E • -tocopherol • antioxidants
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Increasing evidence indicates that oxidative modification of LDL is an important step in the development of atherosclerosis.1 Inhibition of LDL oxidation is hypothesized to prevent the development of atherosclerosis, and therefore antioxidants, especially
-tocopherol (vitamin E) and ß-carotene, the main
antioxidants in LDL particles, have been under intensive investigation.
In human supplementation studies, high doses of
-tocopherol have been reported to decrease in vitro LDL
oxidation.2 3 Studies of the ability of ß-carotene to
prevent oxidation of LDL in vitro have produced contradictory
results,4 5 6 7 and it has been suggested that ß-carotene
acts in the vessel intima by inhibiting LDL oxidation induced by smooth
muscle and endothelial cells.8 9 Intermittent claudication is a clinical manifestation of atherosclerosis in the lower extremities. Studies from the 1950s and 1960s involved treatment of intermittent claudication by administration of vitamin E,10 11 12 but evidence for its efficacy seemed limited and inconsistent. To our knowledge, no clinical trials exist concerning the prevention of intermittent claudication by administration of antioxidants.
The ATBC Cancer Prevention Study was a large-scale study primarily
designed to evaluate the lung cancer–preventive effects of
-tocopherol and ß-carotene
supplementation.13 The study setting also offered the
possibility of studying cardiovascular end points as
well. The aim of the present study was to evaluate whether long-term
supplementation with -tocopherol or ß-carotene
affected the incidence of intermittent claudication.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The subjects of the study reported herein were participants in the ATBC Cancer Prevention Study, a randomized, double-blind, placebo-controlled prevention trial with a 2x2 factorial design that was primarily aimed at examining the effect of
-tocopherol and ß-carotene supplementation on lung
cancer incidence. Participants were recruited from the total male
population aged 50 to 69 years in southwestern Finland (N=290 406).
First, a postal survey was performed to identify current smokers
willing to participate in the trial. Exclusion criteria were prior
malignancy (other than nonmelanoma skin cancer or carcinoma in situ);
severe angina on exertion (Rose criteria, grade 2); chronic renal
failure; cirrhosis of the liver; alcoholism, anticoagulant therapy; or
current use of vitamin E, vitamin A, or ß-carotene supplements in
excess of predefined doses. A total of 29 133 men who smoked 
5
cigarettes per day were thereafter randomly assigned to one of four
groups: dl--tocopherol, 50 mg/d;
ß-carotene, 20 mg/d; dl--tocopherol, 50
mg/d and ß-carotene, 20 mg/d; or placebo. The participants were
enrolled in the study from 1985 through 1988, and the trial
intervention continued until April 30, 1993. The design and methods of
the ATBC Study have been described in detail elsewhere.14
The ATBC Study was approved by the institutional review boards of the
National Public Health Institute, Helsinki, Finland, and the National
Cancer Institute, Bethesda, Md. All subjects provided written, informed
consent before randomization.
We excluded those participants (n=2844) who, at baseline, gave a
history of intermittent claudication as diagnosed by a physician or
reported symptoms of typical intermittent claudication during an
interview based on the London School of Hygiene (Rose) questionnaire on
chest pain and intermittent claudication;15 this procedure
left 26 289 men eligible for this study of the incidence of primary
intermittent claudication. These participants were evenly distributed
at random among the four intervention groups: 6605 in the
-tocopherol, 6552 in the -tocopherol and
ß-carotene, 6559 in the ß-carotene, and 6573 in the placebo group.
Thus, half received -tocopherol (n=13 157) and half did
not (n=13 132); half received ß-carotene (n=13 111) and half did
not (n=13 178).
At baseline, data on background characteristics such as medical and smoking history were collected by questionnaire and checked by specially trained registered nurses. The strenuousness and frequency of the subjects' leisure-time exercise during the previous 12 months were also noted. A self-administered diet history questionnaire was used to measure their usual diet, including alcohol consumption, during the previous 12 months.16 Height and weight were measured. Blood pressure was measured by mercury sphygmomanometry of the right arm while the subject was in a seated position. The lower of two measurements taken at least 1 minute apart was recorded. A blood sample was drawn and serum stored at -70°C. Serum total and HDL cholesterol contents were determined enzymatically (CHOD-PAP method, Boehringer Mannheim, kit No. 124966).17 HDL cholesterol was measured after precipitation with dextran sulfate and MgCl2.18
After randomization the men visited the local study centers every 4 months. Information on physician consultations, self-perceived skin yellowing, current smoking habits, and the use of nonstudy vitamin supplements was collected by questionnaire. At every follow-up visit, the participants returned their remaining capsules and received a new supply. Capsule compliance was assessed as a percentage, calculated by dividing the number of capsules taken by the number of days in the trial. Each man was interviewed annually with the Rose questionnaire on intermittent claudication. The follow-up time of this study lasted until the first occurrence of typical intermittent claudication or the last follow-up visit during which the Rose questionnaire was administered (whichever event occurred first), with a total of 102 530 person-years. If a participant without previous intermittent claudication failed to attend any further follow-up visits when the Rose questionnaire was to be administered, he was considered a dropout and his data were excluded from further analyses.
The first occurrence of typical symptoms of intermittent claudication
was recorded as the end point of this study. Typical intermittent
claudication was defined as pain in one or both calves of the legs that
was induced by exertion and relieved by resting 
10 minutes. Between
consecutive interviews, the proportion for symptoms of typical
intermittent claudication remained consistent and was >50%
throughout follow-up among symptomatic participants. We also used three
alternative end-point criteria to test the effect of end-point
definition on the results. Alternative end-points with fewer cases but
higher specificity were typical intermittent claudication on at least 2
of 3 consecutive questionnaire administrations (n=1046) and severe,
typical intermittent claudication (pain in the calves even while
walking at an ordinary pace on level ground and relieved by rest;
n=1393). For the third alternative, typical and possible intermittent
claudication (pain in one or both calves that was induced by exertion
with no need for rest) were combined and comprised a higher number of
cases but had lower specificity (n=4095).
The incidence of intermittent claudication was calculated by dividing
the number of new events by the cumulative person-years of follow-up
for the four intervention groups separately. Cumulative occurrence
rates of intermittent claudication were calculated by the Kaplan-Meier
method, and overall difference in incidences was tested by the
Mantel-Haenszel method.19 Incidences were also calculated
for -tocopherol compared with no
-tocopherol and for ß-carotene compared with no
ß-carotene, which allowed us to analyze the effect of
-tocopherol and ß-carotene separately, provided that
no significant interaction was observed between them. The Cox
proportional-hazards model was used for estimating crude and adjusted
RRs for the incidence of intermittent claudication.19 We
used the following background variables: age; consumption of
alcohol; frequency and strenuousness of leisure-time physical activity;
number of cigarettes smoked per day (in categories); serum total and
HDL cholesterol; systolic and diastolic
blood pressure; BMI; years of smoking (in tertiles); and history of
diabetes mellitus (dichotomous). The data were stratified across the 14
study areas to avoid any bias due to local differences. For 1819
subjects, data concerning alcohol use were not available. These missing
data were taken into account as one category of alcohol consumption.
Interactions between -tocopherol and ß-carotene, as
well as between the four intervention groups and the background
variables, were tested by the likelihood-ratio test. Interaction
was similarly tested between the intervention groups and the history of
angina pectoris, myocardial infarction, and stroke. In addition,
interaction was tested between self-perceived skin yellowing (as a time
dependent explanatory variable) and the intervention groups. The RR
of dropping out was tested by the Poisson regression.19 We
also tested the proportional-hazards assumption and did not reject
it.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The four intervention groups were well balanced in relation to the baseline characteristics, as shown in Table 1
. The median age at study entry was 57
years, and the men had smoked a median of 20 cigarettes per day for a
median time of 36 years. Mean overall capsule compliance was 94% among
active participants in all intervention groups. The overall dropout
rate was 29.6% and was similar in all intervention groups over time
(29% in the -tocopherol group, 30% in the
-tocopherol and ß-carotene group, 30% in the
ß-carotene group, and 29% in the placebo group; P=.37 for
difference). Several subjects (6%) reported use of nonstudy
supplements containing vitamin E on least at three follow-up visits.
Similarly, 0.7% of subjects reported use of nonstudy ß-carotene.
Supplements were mostly multivitamin preparations with low doses of
-tocopherol (15 mg) and ß-carotene (6 mg).
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During the median 4.0 years of follow-up, we observed 2704 cases of
first occurrence of typical intermittent claudication. The incidence of
intermittent claudication per 1000 person-years was 13% higher in the
-tocopherol group than in the placebo group (95% CI,
1% to 26%), whereas it was only modestly increased in the
-tocopherol and ß-carotene and the ß-carotene only
groups: 4% (95% CI, -7% to 16%) and 5% (95% CI, -5% to 17%),
respectively. The marginally elevated risk for intermittent
claudication among men receiving -tocopherol decreased
to 11% (95% CI, 0% to 24%), however, after adjustment for baseline
characteristics (Table 2). The
Kaplan-Meier curves of incidences in the four intervention groups are
presented in the Figure.
Interactions between -tocopherol and ß-carotene
supplementation in terms of the effect on intermittent claudication did
not reach statistical significance (P=.06).
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For incidences of typical intermittent claudication per 1000
person-years by supplementation with either -tocopherol
or ß-carotene, see Table 3. The
incidence of typical intermittent claudication was 6% higher in those
receiving -tocopherol compared with those who received
no -tocopherol (95% CI, -2% to 14%) and 2% lower in
those receiving ß-carotene compared with those who received no
ß-carotene (95% CI, -9% to 6%). Adjusting for baseline
characteristics affected these results only slightly (Table 3). Among
the baseline characteristics, age, serum total cholesterol,
systolic blood pressure, diabetes mellitus, years of smoking,
and number of cigarettes smoked per day were positively associated with
the incidence of intermittent claudication. Serum HDL
cholesterol and strenuousness of leisure-time physical
activity were inversely associated with risk.
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We also used alternative end points to calculate the adjusted RRs for
intermittent claudication. When we used end points with higher
specificity, ie, typical intermittent claudication on two of three
consecutive interviews or severe typical intermittent claudication, no
significant differences appeared in the risks for intermittent
claudication among men who received -tocopherol compared
with those who did not receive it (Table 4). With these more specific end-point
definitions, adjusted RRs for intermittent claudication were
nonsignificantly lower (by 4% and 10%) among men who received
ß-carotene than those who did not. When typical and possible
intermittent claudication were assessed together, there were no
significant differences in the RRs of either supplementation (Table 4).
No interaction was observed between -tocopherol and
ß-carotene supplementations in their effect on the incidence of
intermittent claudication with any of these alternative end points.
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A history of diabetes significantly modified the effect of
-tocopherol on the incidence of first occurrence of
typical intermittent claudication. Of the incident cases, 209 men had a
baseline history of diabetes (124 received -tocopherol
and 85 did not). Among the subjects with baseline diabetes, the risk of
typical intermittent claudication was 1.50 (95% CI, 1.13 to 1.99)
among those who received -tocopherol compared with those
who had not. On the other hand, among subjects without any baseline
history of diabetes, the adjusted risk of the first occurrence of
typical intermittent claudication was 1.03 (95% CI, 0.95 to 1.11)
among those who received -tocopherol compared with those
who had not. When the incidence of intermittent claudication was
defined by any of the three alternative end points, a history of
diabetes did not modify the effect of supplements. No other
interactions with baseline factors were observed. There was no
interaction of angina pectoris, myocardial infarction, or stroke with
-tocopherol or ß-carotene supplementation in terms of
the incidence of intermittent claudication. Self-perceived skin
yellowing did not modify the effect of either supplement on
claudication.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This large, double-blind, placebo-controlled trial showed no preventive effect of
-tocopherol or ß-carotene
supplementation on the incidence of intermittent claudication, and the
modest increase in the incidence of intermittent claudication among men
who received -tocopherol compared with those who had not
disappeared when we used the alternative definition for claudication
(with higher or lower specificity). A higher number of incident cases
with -tocopherol supplementation seemed to occur only
among men with a history of diabetes, but again, the use of alternative
criteria for claudication removed this association. ß-Carotene
supplementation had no effect on the incidence of intermittent
claudication with any claudication criteria or in any subgroup.
Previous evidence of an association between dietary intake of, serum
levels of, or supplementation with antioxidants and intermittent
claudication is sparse. In a population-based, case-control study, no
relation between intermittent claudication and intake of
-tocopherol and ß-carotene was observed; instead, a
lower intake of vitamin C was found among cases.20 Among
decades-old studies of -tocopherol in the treatment of
intermittent claudication, improvement in the patients' walking
distance was noted in two double-blind, placebo-controlled studies with
high-dose supplementation of synthetic
-tocopherol.11 12 In contrast, no such
effect was observed in a double-blind study with 450 mg of natural
-tocopherol compared with placebo.10 The major
limitation of these studies is small size, only 30 to 40 patients. To
our knowledge, no previous reports exist of prevention or treatment of
intermittent claudication with ß-carotene.
The effects of antioxidant supplementation on other atherosclerotic
conditions are contradictory as well. There are reports of a beneficial
effect,21 no effect,22 or even an adverse
effect13 23 on cardiovascular end points.
Previous analysis in the ATBC Study has shown that
-tocopherol slightly decreased and ß-carotene slightly
increased the incidence of angina pectoris.24
The incidence of typical intermittent claudication in the placebo group
was 24.9/1000 person-years, which is of similar magnitude to that in
previous studies.25 26 Diagnosis was based solely on a
structured questionnaire that was used in an annual interview, and an
incident case was registered when typical symptoms occurred for the
first time. Asymptomatic subjects with lower-extremity
atherosclerosis could not be detected. For intermittent
claudication, fluctuation in symptoms and spontaneous recovery are
typical. This variability in its natural course partly explains the
50% constancy of symptoms of such claudication between consecutive
interviews in our study. For men in a Finnish population with abundant
symptoms of intermittent claudication, the 
-value for repeatability
of typical symptoms evaluated by the Rose questionnaire conducted 6
months apart was .45.27
In the original study by Rose, which was based on 37 patients with intermittent claudication and 18 patients with other leg pain, the sensitivity and specificity of this questionnaire were reported to be high, 92% and 100%, respectively.15 In a larger sample of 586 patients with intermittent claudication and of 61 patients with other leg pain, the sensitivity was 60% and specificity 91%, but when possible claudication was included in the end-point definition, the sensitivity increased to 91% but specificity decreased to 72%.28 In men with typical symptoms of intermittent claudication, clinical examination has revealed significant arterial insufficiency in the lower extremities in only one third.27 In the Edinburgh Artery Study, one third of the men with intermittent claudication (typical and possible, as diagnosed by Rose questionnaire) showed no clinical findings of arterial insufficiency. Among asymptomatic subjects, clinical examination showed 8% with significant and 17% with moderate peripheral atherosclerosis.29 Thus, it is realistic to expect some degree of misclassification of intermittent claudication. Even if there is no reason to believe that misclassification is associated with the supplementation group, it would, however, lead to some degree of underestimation of the supplementation effect.30
One obvious problem is that we were able to obtain data on claudication only from the active participants in the ATBC Study. However, because there were no significant differences in the overall dropout rate among the four intervention groups, we believe that the effect of dropouts on our results was of little importance. Use of nonstudy supplements containing vitamin E or ß-carotene was infrequent and probably had only minor effect on the results.
Diabetes is a strong risk factor for intermittent claudication. In a
5-year follow-up study, the incidence of intermittent claudication was
2.5-fold among non–insulin-dependent diabetic men compared with
nondiabetic control subjects.31 The higher incidence of
claudication among diabetics in the -tocopherol group of
our study contradicts previous expectations of the possible beneficial
effect of antioxidants.32 -Tocopherol
supplementation has been observed to decrease oxidation of glycated LDL
in diabetics,33 but results concerning the effect of
-tocopherol supplementation on glycation of the plasma
proteins, including LDL, are controversial.33 34 35 Our
finding may well be a chance finding due to multiple comparisons,
because with the use of alternative definitions for intermittent
claudication, the effect modification of diabetes disappeared.
The daily dose of 20 mg of ß-carotene increased its serum levels
17-fold,13 a level that can be considered sufficient for a
significant antioxidant effect. On the other hand, daily
supplementation with 50 mg of -tocopherol could be
considered low, but even smaller doses have been reported to increase
the resistance of LDL to oxidation.36 Despite the long
duration of supplementation and excellent compliance, the incidence of
intermittent claudication did not decrease in subjects supplemented
with -tocopherol or ß-carotene, suggesting that
antioxidant vitamins in the doses used in this study do not retard the
progression of atherosclerosis in the lower
extremities.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The ATBC Study was supported by a contract (NOI-CN-45165) from the National Cancer Institute, Bethesda, Md. The present study was supported by the Aarne Koskelo Foundation, Helsinki, Finland.
Received April 21, 1997; accepted August 28, 1997.
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