These data provide no support for the use of these supplements for the prevention of cardiovascular disease in middle-aged and older men.
Despite uncertainty regarding long-term health benefits, most US adults have taken a vitamin supplement in the past year. Basic research studies suggest that vitamin E, vitamin C, and other antioxidants reduce cardiovascular disease by trapping organic free radicals, by deactivating excited oxygen molecules, or both, to prevent tissue damage.
Dietary and supplemental vitamin C have been inconsistently associated with cardiovascular disease, including significant 15 and nonsignificant 16 inverse associations as well no association.
Initial clinical trials of vitamin E alone among male smokers in the Alpha-Tocopherol Beta-Carotene Cancer Prevention ATBC trial showed both possible benefits on prostate cancer 20 and risks on hemorrhagic stroke, 21 in addition to secondary prevention trials such as the Cambridge Heart Antioxidant Study CHAOS , 22 which indicated possible cardiovascular disease reductions. Yet even as largely negative trials of vitamin E later emerged among patients with multiple coronary risk factors or preexisting cardiovascular disease, 23 - 28 vitamin E and other supplement use has remained surprisingly prevalent among healthy individuals who report its regular use as part of their routine health regimen.
Vitamin C has typically been incorporated into antioxidant combinations with vitamin E, beta carotene, and other vitamins and minerals in large-scale clinical trials that reported no significant cardiovascular effects. Therefore, the clinical utility of vitamin C alone in preventing cardiovascular disease among those at low initial risk of cardiovascular disease remains uncertain. Further, because vitamin C may potentially interact with vitamin E, 36 it is important to evaluate the effect of their interaction on cardiovascular disease.
Men were ineligible if they reported a history of cirrhosis, active liver disease, were taking anticoagulants, or reported a serious illness that might preclude participation. A week run-in period excluded noncompliers who typically emerge during the first several months of participation. Men were randomly assigned to vitamin E or its placebo, to vitamin C or its placebo, to beta carotene or its placebo, and to a multivitamin or its placebo.
There were men 5. All participants provided written informed consent and the institutional review board at Brigham and Women's Hospital approved the research protocol.
Participants were sent monthly calendar packs, containing vitamin E or placebo taken every other day , and vitamin C or placebo taken daily , every 6 months for the first year and annually thereafter. Participants also were sent annual questionnaires asking about adherence, potential adverse events, the occurrence of new end points, and updated risk factors. The multivitamin component is still ongoing. Morbidity and mortality follow-up were extremely high at Morbidity and mortality follow-up as a percentage of person-time each exceeded Adherence was defined from participant self-reports as taking at least two-thirds of the study agents.
There were no differences between groups in the average rates of individual nontrial vitamin E supplement use 3.
The primary cardiovascular end point, major cardiovascular events, was a composite end point that included nonfatal MI, nonfatal stroke, and cardiovascular mortality. For each end point reported by participants in the follow-up questionnaire, letter, telephone call, and other correspondence, permission was requested from the participant to examine relevant medical records. Once consent was obtained, records were requested from the hospital or attending physician and reviewed by an end points committee of physicians blinded to randomized treatment assignment.
The diagnosis of MI was confirmed by evidence of symptoms in the presence of either diagnostic elevations of cardiac enzymes or diagnostic changes on electrocardiograms. For fatal events, the diagnosis of MI also was accepted based on autopsy findings. Stroke was classified according to National Survey of Stroke criteria into ischemic, hemorrhagic, and unknown subtype, 41 with high interobserver agreement.
Participant deaths were usually reported by family members or postal authorities. Total mortality was confirmed by the end points committee or by death certificate. Cardiovascular disease mortality was additionally documented by convincing evidence of a cardiovascular mechanism from all available sources, including death certificates, hospital records, and for deaths outside the hospital, observers' impressions. For men with unknown vital status, we used Web searches to identify deaths along with National Death Index searches that included data through End point data also were collected on participant self-reports of congestive heart failure, angina pectoris, and revascularization including coronary artery bypass graft and percutaneous coronary intervention.
All data were analyzed using SAS version 9. Baseline characteristics were first compared by vitamin E or vitamin C treatment assignment to evaluate whether randomization equally distributed baseline characteristics. Whether vitamin E or C adherence affected our primary results was then investigated through sensitivity analyses that censored follow-up when a participant reported taking less than two-thirds of either vitamin E or vitamin C during the previous year.
Finally, subgroup analyses were conducted, stratified by major coronary risk factors, and effect modification was assessed by using interaction terms between subgroup indicators and either vitamin E or vitamin C assignment. At the end of PHS II, there were confirmed major cardiovascular events, including total MIs, total strokes, and cardiovascular deaths, with some men experiencing multiple events. A total of men died during follow-up. The overall rates of major cardiovascular events were There was no effect of vitamin E on the primary end point of major cardiovascular events HR, 1.
Compared with placebo, vitamin E did not reduce the incidence of individual cardiovascular events, including total MI HR, 0. Among stroke subtypes, however, there were 39 hemorrhagic strokes in the active vitamin E group and 23 hemorrhagic strokes in the placebo vitamin E group HR, 1. There was no significant effect of vitamin E on cardiovascular mortality HR, 1. Censoring participants at the time of vitamin E nonadherence did not affect our results for major cardiovascular events HR, 0.
Vitamin E had no effect on the primary prevention of major cardiovascular events events in the active vitamin E group and events in the placebo vitamin E group HR, 1. A statistically significant increased risk of hemorrhagic stroke remained HR, 1. In analyses among the men with baseline cardiovascular disease, there was a nonsignificant reduction in risk of major cardiovascular events HR, 0.
Expanding the definition of baseline cardiovascular disease to add angina pectoris or revascularization among men taking vitamin E still had no effect on major cardiovascular events HR, 0. We also evaluated whether coronary risk factors and each of the other randomized interventions from PHS II modified the effect of vitamin E on major cardiovascular events Table 3. Otherwise, no other significant effect modification by coronary risk factors was found on major cardiovascular events. In addition, there was no effect modification by randomized beta carotene or the ongoing multivitamin treatment assignment.
The overall rates of major cardiovascular events for the active and placebo vitamin C groups were There was no effect of vitamin C on the primary end point of major cardiovascular events HR, 0.
There also was no effect of vitamin C on hemorrhagic stroke. Censoring for nonadherence with vitamin C did not appreciably affect our findings for major cardiovascular events HR, 0. Vitamin C had no effect on the primary prevention of major cardiovascular events events in those receiving active vitamin C and events in those receiving placebo vitamin C HR, 1. In the men with a history of cardiovascular disease at baseline, vitamin C did not affect incident major cardiovascular events HR, 0.
For total MI, there were 18 and 31 cases in the active and placebo vitamin C groups, respectively HR, 0.
Adding angina and revascularization to our definition of baseline cardiovascular disease did not change the lack of effect on major cardiovascular events HR, 1. We then considered whether the effect of vitamin C on major cardiovascular events was modified by baseline coronary risk factors or other PHS II randomized interventions Table 3. No significant effect modification was found between vitamin C and various baseline factors, randomized beta carotene, or the ongoing multivitamin treatment assignment on major cardiovascular events.
We assessed whether vitamin E or vitamin C treatment increased potential adverse effects such as bleeding including hematuria, easy bruising, and epistaxis because vitamin E may potentially inhibit platelet function, 6 along with gastrointestinal tract symptoms peptic ulcer, constipation, diarrhea, gastritis, and nausea , fatigue, drowsiness, skin discoloration or rashes, and migraine. No significant differences were observed in adverse effects, including hematuria, easy bruising, and epistaxis for both active vitamins E and C compared with placebo.
In this large-scale, randomized controlled trial among middle-aged and older men, long-term vitamin E and vitamin C supplement use did not reduce the primary end point of incident major cardiovascular events. We also found that neither vitamin E nor vitamin C reduced total MI, total stroke, cardiovascular death, congestive heart failure, total mortality, angina, or coronary revascularization. We did find an increase in hemorrhagic stroke with vitamin E use. Our finding that vitamin E has no effect on major cardiovascular events, including among a small subgroup of men with a baseline history of cardiovascular disease, is consistent with the majority of previous clinical trials conducted among higher risk individuals with 22 , 24 , 26 , 28 or without 20 , 25 , 26 , 28 preexisting cardiovascular disease.
Although some of these trials report possible reductions in composite cardiovascular end points, 22 , 25 , 28 meta-analyses indicate no overall benefit for vitamin E in the secondary prevention of cardiovascular disease. However, in PHS II we found no significant effect between vitamin E and total mortality after up to 10 years of treatment and follow-up. We used synthetic vitamin E all-rac-alpha-tocopheryl acetate in PHS II, similar to earlier trials, 20 , 24 whereas more recent trials have used natural source vitamin E d -alpha-tocopheryl acetate.
The PHS II represents the first large-scale, long-term trial of individual vitamin C supplementation in the prevention of cardiovascular disease in men. Trials of intermediate cardiovascular end points have yielded inconsistent results.
A combination of vitamins that included vitamin C had no effect on the rate and severity of restenosis in one trial. Adherence is of potential concern in any clinical trial. However, adherence remained high in PHS II during up to 10 years of follow-up, with low drop-in use in all of the study groups. Sensitivity analyses that censored follow-up time based on nonadherence did not alter our findings.
Although PHS II represents one of the longest trials to date of individual vitamin E and vitamin C use on cardiovascular disease, an even longer period of vitamin supplementation may be necessary to cover the critical etiologic window or provide a sufficient cumulative dose capable of preventing cardiovascular disease. Vitamins E and C represent 2 parts of a broader spectrum of essential vitamins and minerals with possible roles in cardiovascular disease prevention.
The randomized multivitamin component of PHS II still continues, with total treatment and follow-up planned to last more than a decade. These data provide no support for the use of these supplements in the prevention of cardiovascular disease in middle-aged and older men. Drs Sesso and Gaziano had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses.
Analysis and interpretation of data: Critical revision of the manuscript for important intellectual content: Administrative, technical, or material support: Dr Manson reported receiving investigator-initiated research funding from the National Institutes of Health and assistance with study pills and packaging from BASF and Cognis. Dr Gaziano reported receiving investigator-initiated research funding from the National Institutes of Health, the Veterans Administration, Veroscience and Amgen; serving as a consultant or receiving honoraria from Bayer AG and Pfizer; and serving as an expert witness for Merck.
No other authors reported financial disclosures. Role of the Sponsors: BASF, Wyeth Pharmaceuticals, and DSM Nutritional Products Inc had no role in the study design; conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
Data and Safety Monitoring Board: Dr Gaziano, a contributing editor for JAMA , was not involved in the editorial review of or decision to publish this article. The result was a more elegant design, but also made more rigorous and that of their previous projects Case Study. Like its predecessor, the No. Surrounded by a forest characteristic of the whole area was built on a site that offers a wide view across the hill in Miradero Road, Beverly Hills, California, USA. With a simple and rectangular, in a wing is the master bedroom and two smaller, center, lounge and music room, and in the opposite wing, kitchen, breakfast area, the covered porch, the and the dining hall.
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