JAMA: Vitamin E, A, beta-caro increases mortality

The Journal of the American Medical Association: is an international peer-reviewed Medical Journal (arguably the most highly influential; or at least among the top three in that area). Here is some information from Wikipedia that appears to be accurate (for those of us who may be unaware, it appears anyone online can edit Wikipedia pages):

JAMA: The Journal of the American Medical Association is an international peer-reviewed general medical journal, published 48 times per year by the American Medical Association. JAMA is the most widely circulated medical journal in the world.[1]

Founded in 1883 by the American Medical Association and published continuously since then, JAMA publishes original research, reviews, commentaries, editorials, essays, medical news, correspondence, and ancillary content (such as abstracts of the Morbidity and Mortality Weekly Report). In 2005, JAMAs impact factor was 23.5[1] placing it among the leading general medical journals.[2] JAMAs acceptance rate is approximately 8% of the nearly 6000 solicited and unsolicited manuscripts it receives annually.[1] The first editor was Nathan Smith Davis, the founder of the American Medical Association and present editor of JAMA is Catherine DeAngelis, MD

Some information on the AMA (the publisher of JAMA) from Answers.com, provided by US History Encyclopedia:

American Medical Association

American Medical Association (AMA) was founded on 7 May 1847 as a response to the growing demands for reforms in medical education and practice. Dr. Nathan S. Davis (1817–1904), a delegate from the New York State Medical Society who later came to be known as the "founding father of the AMA," convened a national conference of physicians to address reforms in medical education, medical ethics, and public health. On 7 May 1847 more than 250 physicians from more than forty medical societies and twenty-eight medical colleges assembled in the Great Hall of the Academy of Natural Sciences in Philadelphia and established the American Medical Association. A Committee on Medical Education was appointed, and minimum standards of medical education were established. The first national code of American medical ethics, the cornerstone of professional self-regulation, was adopted. Written by Dr. John Bell (1796–1872) and Dr. Isaac Hays (1796–1879) and published in 1847, the Code of Medical Ethics of the American Medical Association provided guidelines for the behavior of physicians with respect to patients, society, and other medical professionals.

Throughout the nineteenth century the AMA worked to expose fraudulent and unethical practitioners and to limit licensure to allopathic physicians. In 1883 the Journal of the American Medical Association (JAMA) was established with Nathan Davis as the first editor. By 1901, JAMA was reporting a circulation of 22,049 copies per week, the largest of all medical journals in the world.

Membership, however, remained small, including only 10,000 of the 100,000 orthodox physicians. In 1901 the AMA underwent a major reorganization to become a more effective national body by providing proportional representation among state medical societies. The House of Delegates was established as the legislative body of the AMA. Each state society was allowed a specific number of delegates with voting rights. By 1906, membership in the AMA exceeded 50,000 physicians, and educational and licensing reforms began to take hold.

The newly established Council on Medical Education inspected 160 medical schools (1906–1907), and in 1910 the Flexner Report, Medical Education in the United States and Canada, was published. Funded by the Carnegie Foundation and supported by the AMA, the report exposed the poor conditions of many schools and recommended implementing rigorous standards of medical training. By 1923 the AMA had adopted standards for medical specialty training, and in 1927 the association published a list of hospitals approved for residency training.

By World War I, the AMA had become a powerful political lobby. Wary of governmental control, it fought proposals for national health insurance. The 1935 Social Security Act passed without compulsory health insurance due to AMA influence. Physician membership grew steadily to over 100,000 physicians by 1936. The AMA continued to fight government involvement in health care with a campaign against President Truman's initiatives in 1948. In 1961 the American Medical Political Action Committee (AMPAC) was formed to represent physicians' and patients' interests in health care legislation.

The AMA continued to work on numerous public health initiatives, including declaring alcoholism to be an illness (1956), recommending nationwide polio vaccinations (1960), and adopting a report on the hazards of cigarette smoking (1964). AMA membership exceeded 200,000 physicians by 1965. From 1966 to 1973, the AMA coordinated the Volunteer Physicians in Vietnam program and in 1978 supported state legislation mandating use of seat belts for infants and children.

In 1983, membership included 250,000 physicians. As AIDS became an epidemic in the 1980s, the AMA passed a resolution opposing acts of discrimination against AIDS patients (1986) and established the office of HIV/AIDS (1988).

By 1990, health maintenance organizations (HMOs) and other third-party payers were involved extensively in health care delivery. Health care reform had become a political priority. In 1994 and 1995 the AMA drafted two Patient Protection Acts, and in 1998 the AMA supported the Patient's Bill of Rights.

In 2001, AMA membership included 300,000 physicians. As new threats to the nation's health, such as bioterrorism, began to emerge in the twenty-first century, the AMA continued to rely on the principles in the AMA Code of Medical Ethics (revised 2001) and the democratic process of the AMA House of Delegates to guide its actions and policies to fulfill its mission as "physicians dedicated to the health of America."

Bibliography

Baker, Robert B., et al. The American Medical Ethics Revolution: How the AMA's Code of Ethics Has Transformed Physicians' Relationships to Patients, Professionals, and Society. Baltimore: Johns Hopkins University Press, 1999.

Duffy, John. From Humors to Medical Science: A History of American Medicine. Chicago: University of Illinois Press, 1993.

Starr, Paul. The Social Transformation of American Medicine: The Rise of a Sovereign Profession and the Making of a Vast Industry. New York: Basic Books, 1982.

Stevens, Rosemary. American Medicine and the Public Interest: A History of Specialization. Berkeley, Calif.: University of California Press, 1998.

Here is the abstract:

Vol. 297 No. 8, February 28, 2007
Review 

Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention
Systematic Review and Meta-analysis

Goran Bjelakovic, MD, DrMedSci; Dimitrinka Nikolova, MA; Lise Lotte Gluud, MD, DrMedSci; Rosa G. Simonetti, MD; Christian Gluud, MD, DrMedSci

JAMA. 2007;297:842-857.

Context  Antioxidant supplements are used for prevention of several diseases.

Objective  To assess the effect of antioxidant supplements on mortality in randomized primary and secondary prevention trials.

Data Sources and Trial Selection  We searched electronic databases and bibliographies published by October 2005. All randomized trials involving adults comparing beta carotene, vitamin A, vitamin C (ascorbic acid), vitamin E, and selenium either singly or combined vs placebo or vs no intervention were included in our analysis. Randomization, blinding, and follow-up were considered markers of bias in the included trials. The effect of antioxidant supplements on all-cause mortality was analyzed with random-effects meta-analyses and reported as relative risk (RR) with 95% confidence intervals (CIs). Meta-regression was used to assess the effect of covariates across the trials.

Data Extraction  We included 68 randomized trials with 232 606 participants (385 publications).

Data Synthesis  When all low- and high-bias risk trials of antioxidant supplements were pooled together there was no significant effect on mortality (RR, 1.02; 95% CI, 0.98-1.06). Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality. In 47 low-bias trials with 180 938 participants, the antioxidant supplements significantly increased mortality (RR, 1.05; 95% CI, 1.02-1.08). In low-bias risk trials, after exclusion of selenium trials, beta carotene (RR, 1.07; 95% CI, 1.02-1.11), vitamin A (RR, 1.16; 95% CI, 1.10-1.24), and vitamin E (RR, 1.04; 95% CI, 1.01-1.07), singly or combined, significantly increased mortality. Vitamin C and selenium had no significant effect on mortality.

Conclusions Treatment with beta carotene, vitamin A, and vitamin E may increase mortality. The potential roles of vitamin C and selenium on mortality need further study.

Author Affiliations: The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark (Drs Bjelakovic, L. L. Gluud, Simonetti, and C. Gluud and Ms Nikolova); Department of Internal Medicine, Gastroenterology and Hepatology, University of Nis, Nis, Serbia (Dr Bjelakovic); and Divisione di Medicina, Ospedale V. Cervello, Palermo, Italy (Dr Simonetti).

This was (believe it or not, conspiracy theorists) a contraversial publication, and it appears 4 [four] related letters published!

Disclaimer: I need to take a look at those four [4] related replies; my tentative conclusion is so far based on only this one publication, and not the following letters; I haven't had time yet to investigate these yet.

1. Antioxidant Supplements and Mortality
Demetrius Albanes
JAMA. 2007;298:400. (July 25, 2007)

2. Antioxidant Supplements and Mortality
Harri Hemilä
JAMA. 2007;298:401. (July 25, 2007)

3. Antioxidant Supplements and Mortality
Philip R. Taylor and Sanford Dawsey
JAMA. 2007;298:401-402. (July 25, 2007)

4. Antioxidant Supplements and Mortality—Reply
Lise Lotte Gluud, Goran Bjelakovic, Dimitrinka Nikolova, Rosa G. Simonetti, and Christian Gluud
JAMA. 2007;298:402-403. (July 25, 2007)

Not being a licenced physician myself, here are my thoughts:

I must say that after viewing parts of the full text and the investigators selection criteria etc. that this evidence strongly suggests that Vitamin E supplementation has no significant overall effect on mortality. I've read before that there may be overall increases in mortality; and that could, I assume, be due to mega-dosing (i.e. far exceeding 100% US RDA, heavy metals such as lead, cadnium, other heavy metals -- also other impurities may exist, depending on the case).

Since alpha-tocopherol seems to be what is most commonly investigated and is used in the trials cited in the research above, it seems this evidence makes it to be a fair conclusion that alpha-tocopherol alone isn't effective at extending human lifespan.

The Linus Pauling Institute described vitamin E as: "a family of eight antioxidants, four tocopherols, alpha-, beta-, gamma- and delta-, and four tocotrienols (also alpha-, beta-, gamma- and delta-). Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore, the form of vitamin E found in the largest quantities in the blood and tissue (1). Because alpha-tocopherol is the form of vitamin E that appears to have the greatest nutritional significance, it will be the primary topic of the following discussion. It is also the only form that meets the latest Recommended Dietary Allowance (RDA) for vitamin E."

It seems LPI is saying that alpha is the only vitamer worth investigating. However, I've heard it said before that if the studies included for meta-analysis used different proportions of four tocopherols, alpha-, beta-, gamma- and delta-, and four tocotrienols -- also alpha-, beta-, gamma- and delta-, we'd likely get different results; however, lacking in evidence, it seems no conclusion can be drawn at this point; right?

I don't know what this means, really -- for each individual who considers taking multi-vitamin supplements fortified with vitamin E (and if it's true that (as LPI says): "Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body," then the other forms are useless, right?).

http://lpi.oregonsta...amins/vitaminE/

It seems it's best to get your vitamins through a healthy diet rather than gamble with pills of unknown efficacy; not to mention impurities.

I guess I can safely say (I am not a doctor though) that individuals who may not get adequate vitamin E in their diet might need a Vitamin E supplement, and prenatal vitamins sound like a good idea. Personally, due to this evidence, I am now concerned that exceeding 100% vitamin e per day may even shorten lifespan for many individuals. Similarly, it seems the same effect may exist in beta carotene and vitamin A, so, in accordance with this new evidence exceeding 100% RDA may seem be risky too. It appears vitamin C and selenium need further study.

Thoughts or comments, anyone?

Take care.

Meta-regression was used to assess the effect of covariates across the trials.

It is highly probable that that there is a causality from vitamin intake to all-cause mortality. But could, nevertheless, the fact that e.g. a majority of people take vitamins because they have some form of disorder cause a more or less constant bias to all analysed studies that has been ignored? My statistical skills are rusted, so what do you think? I guess one should look at the details of the reports to find out.

Edit:
Hmm, I should read better before posting..... [lol]

From the first reply:

Based on their meta-analysis of antioxidant supplementation trials, Dr Bjelakovic and colleagues1 conclude that some of the intervention nutrients appeared to be associated with increased mortality. Particular aspects of their approach, analysis, and reported findings may have led to incomplete or biased determinations of the real effect of such nutrients in various populations.

Second:

We have several concerns about the meta-analysis of randomized trials of antioxidant supplements by Dr Bjelakovic and colleagues.1 First, establishing causality requires considering temporal relationship, dose-response relationship, evidence of supplement use, effects that disappear after discontinuation of supplementation, lack of alternative explanations, and recurrence after restarting supplement use. It is difficult to establish a causal relationship between supplement use and risk of death when 2 of the criteria (response to rechallenge and response to discontinuation of use) cannot be applied to the outcome of death. Hence, greater reliance must be placed on plausible biological mechanisms and evidence that nutrients affect specific disorders. As the authors pointed out, it is likely that increased cancer and cardiovascular mortality are the main reasons for the increased all-cause mortality. The review would have been more convincing if it had also addressed cause-specific mortality.

Third:

We believe that the approach used in the meta-analysis of mortality in randomized trials of antioxidant supplements by Dr Bjelakovic and colleagues1 erred in several important ways, probably resulting in biased conclusions.

Fourth, the defence, but blahblah to me....:

Dr Albanes and Dr Huang and colleagues stress the potential importance of trials with 0 events. In our primary analyses, we calculated RRs and therefore excluded trials with 0 events (405 trials with 40 000 participants). Sensitivity analyses including 1 hypothetical trial with 1 death in each study arm and 40 000 participants reached the same conclusion as the primary analysis (RR, 1.02; 95% CI; 0.98-1.06). Trials with 0 events are likely to have specific characteristics (eg, short duration, low dose). We did not use imputation techniques because they are based on the assumption that any trial can be replaced by a new randomly chosen trial in the same sample.

Edited by brainbox, 06 August 2007 - 12:00 AM.

Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

It is an interesting result, and there have been a few other studies (mainly regarding single antioxidants) that have shown little or no effect on mortality. However, I am not a big fan of population studies or meta-analyses because of the inumerable lifestyle co-factors that are hard to control for and because there is never an answer to the "why". What is the physiological effect within the body that is increasing or decreasing mortality?

I don't know what this means, really -- for each individual who considers taking multi-vitamin supplements fortified with vitamin E (and if it's true that (as LPI says): "Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body," then the other forms are useless, right?). 

The others are passively maintained. Alpha is a small fraction of dietary E, but is vital to prevent fetal resorption, so evolution gave us a mechanism to preferentially maintain alpha. So you screw up the balance by stacking the diet with alpha and the others get displaced.

But could, nevertheless, the fact that e.g. a majority of people take vitamins because they have some form of disorder cause a more or less constant bias to all analysed studies that has been ignored?

Good question, but the answer is no. Only randomized trials were taken into account. This means who gets vitamins and who gets placebo is determined by lottery.

This JAMA Meta Analysis has been harshly critisized, by reputable persons. Search fo yourself with some of the following as keywords

Professor Balz Frei, Linus Pauling Institut Oregon State University:
“The “meta-analysis” published in JAMA, which is a statistical analysis of previously published data, looked at 815 antioxidant trials but included only 68 of them in its analysis, and two of the studies excluded – which were published in the Journal of the National Cancer Institute and the prominent British medical journal Lancet – found substantial benefits and reduced mortality from intake of antioxidant supplements.
If these two large studies had been included, none of the reported effects on increased mortality would have been significant, with the exception of the effects of beta carotene. And the research showing a higher incidence of lung cancer in smokers who take supplements of beta carotene or vitamin A is old news, that’s been known for many years. Very high doses of vitamin A are known to have multiple adverse health effects.”

Professor Meir Stampfer Harvard School of Public Health: "This study does not advance our understanding, and could easily lead to misinterpretation of the data.”
Professor Jeffrey Blumberg, Director of the Antioxidants Research Laboratory Tufts University Boston, Massachusetts: “One of the major premises of doing such a meta-analysis is that the studies should be comparable…here, they looked at primary prevention, treatment, old people, young people, smokers, non-smokers. Only when they used their own criteria of what was good and what was bad were they able to show an increase in all-cause mortality"

Dr. Steve Hickey Staffordshire – and Manchester University, PDF here: www.alliance-natural-health.org/_docs/ANHwebsiteDoc_270.pdf

etc. etc.

This analysis is really an example of bad science. I have read elsewhere (source is in german), that the NEJM has rejected the paper before.

Although it is an ad hominem argument and should not be the first argument, it seems that Bjelakovic et al. are on a mission.


http://lpi.oregonstate.edu
http://www.newsvine....you-live-longer
http://www.washingto...7022700925.html

Edited by markymark, 08 August 2007 - 09:03 AM.

Disclaimer: I need to take a look at those four [4] related replies; my tentative conclusion is so far based on only this one publication, and not the following letters; I haven't had time yet to investigate these yet.

1.  Antioxidant Supplements and Mortality
Demetrius Albanes
JAMA. 2007;298:400. (July 25, 2007)

2.  Antioxidant Supplements and Mortality
Harri Hemilä
JAMA. 2007;298:401. (July 25, 2007)

3.  Antioxidant Supplements and Mortality
Philip R. Taylor and Sanford Dawsey
JAMA. 2007;298:401-402. (July 25, 2007)

4.  Antioxidant Supplements and Mortality—Reply
Lise Lotte Gluud, Goran Bjelakovic, Dimitrinka Nikolova, Rosa G. Simonetti, and Christian Gluud
JAMA. 2007;298:402-403. (July 25, 2007)

Not being a licenced physician myself, here are my thoughts:

I must say that after viewing parts of the full text and the investigators selection criteria etc. that this evidence strongly suggests that Vitamin E supplementation has no significant overall effect on mortality.  I've read before that there may be overall increases in mortality; and that could, I assume, be due to mega-dosing (i.e. far exceeding 100% US RDA, heavy metals such as lead, cadnium, other heavy metals -- also other impurities may exist, depending on the case).

Since alpha-tocopherol seems to be what is most commonly investigated and is used in the trials cited in the research above, it seems this evidence makes it to be a fair conclusion that alpha-tocopherol alone isn't effective at extending human lifespan.

The Linus Pauling Institute described vitamin E as: "a family of eight antioxidants, four tocopherols, alpha-, beta-, gamma- and delta-, and four tocotrienols (also alpha-, beta-, gamma- and delta-). Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body and is therefore, the form of vitamin E found in the largest quantities in the blood and tissue (1). Because alpha-tocopherol is the form of vitamin E that appears to have the greatest nutritional significance, it will be the primary topic of the following discussion. It is also the only form that meets the latest Recommended Dietary Allowance (RDA) for vitamin E."

It seems LPI is saying that alpha is the only vitamer worth investigating.  However, I've heard it said before that if the studies included for meta-analysis used different proportions of four tocopherols, alpha-, beta-, gamma- and delta-, and four tocotrienols -- also alpha-, beta-, gamma- and delta-,  we'd likely get different results; however, lacking in evidence, it seems no conclusion can be drawn at this point; right?

I don't know what this means, really -- for each individual who considers taking multi-vitamin supplements fortified with vitamin E (and if it's true that (as LPI says): "Alpha-tocopherol is the only form of vitamin E that is actively maintained in the human body," then the other forms are useless, right?). 

http://lpi.oregonsta...amins/vitaminE/

It seems it's best to get your vitamins through a healthy diet rather than gamble with pills of unknown efficacy; not to mention impurities.

I guess I can safely say (I am not a doctor though) that individuals who may not get adequate vitamin E in their diet might need a Vitamin E supplement, and prenatal vitamins sound like a good idea.  Personally, due to this evidence, I am now concerned that exceeding 100% vitamin e per day may even shorten lifespan for many individuals.  Similarly, it seems the same effect may exist in beta carotene and vitamin A, so, in accordance with this new evidence exceeding 100% RDA may seem be risky too.  It appears vitamin C and selenium need further study.

Thoughts or comments, anyone?

Take care.

Update: I haven't yet evaluated the four replies to the JAMA meta-analysis cited above (if anyone else has, please report) -- however, there was a study published online today in JNCI that might help provide evidence that vitamins and minerals are ineffective at reducing liver cancer incidence. So in other words, I think the following evidence suggests that vitamins and minerals have no measurable effect on whether or not you get liver cancer. What might this suggest for vitamin/mineral combinations for other types of cancers?

Here's some information regarding the primary source provided by the National Institutes of Health (NIH) -- U.S. Department of Health and Human Services:

The Journal of the National Cancer Institute:

Mission

The National Cancer Institute is the world’s largest organization solely dedicated to cancer research.

NCI supports researchers at universities and hospitals across the United States and at NCI-Designated Cancer Centers, a network of facilities that not only study cancer in laboratories, but conduct research on the best ways to rapidly bring the fruits of scientific discovery to cancer patients.

In NCI’s own laboratories, almost 5,000 principal investigators, from basic scientists to clinical researchers, conduct earliest phase cancer clinical investigations of new agents and drugs. Recent advances in bioinformatics and the related explosion of technology for genomics and proteomics research are dramatically accelerating the rate for processing large amounts of information for cancer screening and diagnosis. The largest collaborative research activity is the Clinical Trials Program for testing interventions for preventing cancer, diagnostic tools, and cancer treatments, allowing access as early as possible to all who can benefit. NCI supports over 1,300 clinical trials a year, assisting more than 200,000 patients.

NCI’s scientists also work collaboratively with extramural researchers in order to accelerate the development of state-of-the-art techniques and technologies. In addition to direct research funding, NCI offers the Nation's cancer scientists a variety of useful research tools and services, including tissue samples, statistics on cancer incidence and mortality, bioinformatic tools for analyzing data, databases of genetic information, and resources through NCI-supported Cancer Centers, Centers of Research Excellence, and the Mouse Models of Human Cancer Consortium. NCI researchers are also seeking the causes of disparities among underserved groups and gaps in quality cancer care, helping to translate research results into better health for groups at high risk for cancer, including cancer survivors and the aging population.

As the leader of the National Cancer Program, NCI provides vision and leadership to the global cancer community, conducting and supporting international research, training, health information dissemination, and other programs. Timely communication of NCI scientific findings help people make better health choices and advise physicians about treatment options that are more targeted and less toxic.

Information about the National Cancer Institute's research and activities is available through its Web site, http://cancer.gov.

Here's the study abstract:

Journal of the National Cancer Institute Advance Access published online on August 8, 2007
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djm084

Published by Oxford University Press 2007.

--------------------------------------------------------------------------------

Chemoprevention of Primary Liver Cancer: A Randomized, Double-Blind Trial in Linxian, China

Chen-Xu Qu, Farin Kamangar, Jin-Hu Fan, Binbing Yu, Xiu-Di Sun, Philip R. Taylor, Bingshu E. Chen, Christian C. Abnet, You-Lin Qiao, Steven D. Mark, Sanford M. Dawsey
Affiliations of authors: Cancer Institute, Chinese Academy of Medical Sciences, Beijing, China (CXQ, JHF, XDS, YLQ); Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (FK, PRT, BEC, CCA, SMD); Information Management Services, Silver Spring, MD (BY); Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, CO (SDM)

Correspondence to: Farin Kamangar, MD, PhD, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Rm 3034, Bethesda, MD 10892-7232 (e-mail: kamangaf@mail.nih.gov) or You-Lin Qiao, MD, PhD, Department of Cancer Epidemiology, Cancer Institute, Chinese Academy of Medical Sciences, PO Box 2258, Beijing 100021, People’s Republic of China (e-mail: qiaoy@public.bta.net.cn).

Background: Primary liver cancer is a common malignancy with a dismal prognosis. New primary prevention strategies are needed to reduce mortality from this disease. We examined the effects of supplementation with four different combinations of vitamins and minerals on primary liver cancer mortality among 29450 initially healthy adults from Linxian, China.

Methods: Participants were randomly assigned to take either a vitamin–mineral combination ("factor") or a placebo daily for 5.25 years (March 1986–May 1991). Four factors (at doses one to two times the US Recommended Daily Allowance)—retinol and zinc (factor A); riboflavin and niacin (factor B); ascorbic acid and molybdenum (factor C); and beta-carotene, alpha-tocopherol, and selenium (factor D)—were tested in a partial factorial design. The study outcome was primary liver cancer death occurring from 1986 through 2001. Adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of liver cancer death with and without each factor. All P values are two-sided.

Results: A total of 151 liver cancer deaths occurred during the analysis period. No statistically significant differences in liver cancer mortality were found comparing the presence and absence of any of the four intervention factors. However, both factor A and factor B reduced liver cancer mortality in individuals younger than 55 years at randomization (HR = 0.59, 95% CI = 0.34 to 1.00, and HR = 0.54, 95% CI = 0.31 to 0.93, respectively) but not in older individuals (HR = 1.06, 95% CI = 0.71 to 1.59, and HR = 1.12, 95% CI = 0.75 to 1.68, respectively). Factor C reduced liver cancer death, albeit with only borderline statistical significance in males (HR = 0.70, 95% CI = 0.47 to 1.02) but not in females (HR = 1.30, 95% CI = 0.72 to 2.37). Cumulative risks of liver cancer death were 6.0 per 1000 in the placebo arm, 5.4 per 1000 in the arms with two factors, and 2.4 per 1000 in the arm with all four factors.

Conclusion: None of the factors tested reduced overall liver cancer mortality. However, three factors reduced liver cancer mortality in certain subgroups.

--------------------------------------------------------------------------------

CONTEXT AND CAVEATS
Prior knowledge

Liver cancer is relatively common, and the death rate from the disease is high. Several possible chemoprevention strategies are being investigated, including nutritional chemoprevention.

Study design

The Linxian General Population Trial was a randomized factorial intervention trial that examined the effects of four vitamin–mineral combinations ("factors"), taken for 5.25 years, on incidence of and mortality from several cancers in a Chinese population with inadequate intake of multiple vitamins and minerals. Follow-up (an average of nearly 13 years) is now sufficient to examine liver cancer mortality.

Contribution

None of the factors reduced mortality from liver cancer overall. However, some factors reduced liver cancer mortality in subgroups defined by age or sex.

Implications

In populations with poor nutrition, certain subgroups may experience reduced liver cancer mortality if they take certain nutritional supplements.

Limitations

Some of the results, including the subgroup findings, may have arisen by chance. Because each intervention factor was a combination of several vitamins and minerals, it was not possible to evaluate the independent effect of each vitamin or mineral. The population of Linxian may not be representative of other populations, especially vitamin-replete populations.

Manuscript received November 27, 2006; revised June 6, 2007; accepted June 27, 2007.

To live the longest and healthiest life, it seems a healthy diet in combination with exercise is the most evidence based way to go.

Click here to see how diet and/or exercise may affect cancer; whether or not you've already got it. But hey, we're not just discussing cancer incidence here, we're discussing mortality rates in this topic; essentially we are discussing whether or not particular vitamins increase lifespan or not, right? Because if the results from cancer incidence are the same for healthy folks, healthy diet and exercise are the winning combination and the pills are still in the "hype" category, however unfortunate that may be for those of us taking them. Is it too easy to assume taking pills and powders in place of foods could have the same effect? Is perhaps taking vitamins and minerals worthless, or even dangerous?

Thoughts or comments? Evidence, please.

Take care.

Whoops, I just noticed this:

CONTEXT AND CAVEATS
Prior knowledge

Liver cancer is relatively common, and the death rate from the disease is high. Several possible chemoprevention strategies are being investigated, including nutritional chemoprevention.

Study design

The Linxian General Population Trial was a randomized factorial intervention trial that examined the effects of four vitamin–mineral combinations ("factors"), taken for 5.25 years, on incidence of and mortality from several cancers in a Chinese population with inadequate intake of multiple vitamins and minerals. Follow-up (an average of nearly 13 years) is now sufficient to examine liver cancer mortality.

Contribution

None of the factors reduced mortality from liver cancer overall. However, some factors reduced liver cancer mortality in subgroups defined by age or sex.

Implications

In populations with poor nutrition, certain subgroups may experience reduced liver cancer mortality if they take certain nutritional supplements.

Limitations

Some of the results, including the subgroup findings, may have arisen by chance. Because each intervention factor was a combination of several vitamins and minerals, it was not possible to evaluate the independent effect of each vitamin or mineral. The population of Linxian may not be representative of other populations, especially vitamin-replete populations.

Manuscript received November 27, 2006; revised June 6, 2007; accepted June 27, 2007.

So if you live in a population with "poor nutrition," it seems it might be a good idea to take a multivitamin/mulitmineral should you wish to reduce liver cancer mortality incidence.

I'm not out here concluding either way that vitamins and/or mineral pills are or aren't effective at allowing humans to live longer or shorter or reducing and/or fighting cancer incidence; let's allow the strongest evidence provide the conclusions; at this time, it seems a lot of research has been conducted that provides no worthwhile conclusion either way; in fact, it seems the largest body of evidence suggests vitamin and/or mineral pills may be at best a waste of money and at worst possibly dangerous. Unless you live in a population with poor nutrition. I am a vegetarian (I don't force it on others though); so I do take several supplements to compensate for what I may miss out on.

I am still going to examine those four replies and the comments by individuals in this topic. Any further evidence-based thoughts or comments would be welcomed.

Take care.

I took a look at what The Journal of the American Nutraceutical Association had to say about this study; and what they said makes some sense. Because I am NOT a physician myself, I tend to try to be as skeptical as possible when evaluating evidence.

Bernd Wollschlaeger, M.D.,F.A.A.F.P., an Integrative MD I would recommend, is also an editor at this journal.

Here is an excerpt of their report on the JAMA publication:

JAMA’s “Anti”- Antioxidant Study
Mark Houston, MD, MS*
Associate Clinical Professor of Medicine, Vanderbilt University School of Medicine
Director, Hypertension Institute, Nashville Tennessee
Editor-in-Chief, JANA
Nadine Taylor, MS, RD
Chair, Women’s Health Advisory Council,
American Nutraceutical
Associate Editor, JANA

Like millions of health-conscious Americans, we were troubled (although not exactly panicked) by the meta-analysis published in the February, 2007 edition of the Journal of the American Medical Association, proclaiming that antioxidants were not only ineffective at reducing mortality, but (in the case of vitamins A and E) might actually increase it!1 Our first instinct was to be suspicious: a wealth of scientific evidence shows that antioxidants are vitally important disease fighters, immune boosters and promoters of good health. And as we looked more closely at the study, we found that our instincts were correct. The study used flawed premises to produce a flawed finding.
...

But perhaps the biggest flaw of all in the JAMA study lies in the merging of studies of healthy people with those of unhealthy people to come up with an overall mortality risk. The study population makes a huge difference in the outcome.  Combining these two groups automatically skews the results, as the risk of death in the chronically ill is inherently much higher than it is in healthy people. Plus, no one has ever claimed that antioxidants can prevent death in those who are seriously ill. Lumping together the death rates from both of these groups to come up with a link between antioxidant use and the risk of mortality is simply bad science.

...

I tend to agree that there's a big problem if we're: "merging of studies of healthy people with those of unhealthy people to come up with an overall mortality risk" -- that's the same problem we have with compounds such as Piracetam and other purported "nootropics"! Not to mention, the older studies examining the efficacy of purported nootropics use scales that are now considered worthless compared to modern tools such as the CANTAB Battery; unfortunately (that's probably quite ironic to hear from me -- the same dude who highlighted only the positive findings of such studies in huge fonts and multi colors -- only to go back and make them invisible when I realized some of my high school friends might have been paying attention [tung] -- not to mention Doctors who are cognizant of the state of the research...and modafinil)

Anyways, the point is -- I think -- if we're "healthy" (i.e. we come out O.K. from our annual physical, annual or bi-annual Complete Blood Count, differential, platelet count, Comprehensive Metabolic Panel; hey, why not test your blood levels of heavy metals considering 1 in 4 New Yorkers has elevated blood mercury, and half of multi-vitamins have high lead content), we should probably be examining only evidence from healthy subjects, right?

Well, I might think so. However, why not mix the results? Couldn't that tell us how the entire population responds? I mean, if mortality rates are increased in non-healthy subjects from vitamins, that's not good news either, right?

And with respect to "cherry picking" evidence, wouldn't you agree that it's best to select evidence from what physicians consider low bias? What is low-bias? My opinion of "low bias" would be probably be studies that weren't funded by supplement firms, to start. What do you consider low-bias?

Thoughts or comments?

Take care.

Edit: correction -- " -- no quality evidence in healthy subjects" was referring not to evidence from multivitamin use. The "same problem" I was trying to address the "problem" of mixing results of healthy subjects and other groups.

Edited by adam_kamil, 10 August 2007 - 07:31 PM.

Upon further investigation, I found a letter at The American Journal of Clinical Nutrition; published last month that reports on the efficacy of vitamin E quite appropriately.

However, first, for my fellow laymen and women, may I please present some introductory information regarding the American Society for Nutrition -- provided by the U.S. Department of Health and Human Services?

Here ya go:

American Society for Nutrition - ASN

Organization URL(s)

sec@nutrition.org
www.nutrition.org

Other Contact Information

9650 Rockville Pike, Suite L-4500
Bethesda, MD 20814

301-634-7050 (Voice)
301-634-7892 (FAX)

Description

The American Society for Nutrition (3,500, members) is the premier research society dedicated to improving the quality of life through the science of nutrition. The Society fulfills its mission via the following: fostering and enhancing research in animal and human nutrition; providing opportunities for sharing, disseminating, and archiving peer-reviewed nutrition research results (at its annual meeting and in its official publications, The Journal of Nutrition and the American Journal of Clinical Nutrition); fostering quality education and training in nutrition; upholding standards for ethical behavior in research, the protection of human subjects, and the care and treatment of research animals; providing opportunities for fellowship and support among nutritionists; and bringing scientific knowledge to bear on nutrition issues through communication and influence in the public domain.
Print Resources

The American Society for Nutrition publishes "The American Journal of Clinical Nutrition" and "The Journal of Nutrition."

Here is a relevant excerpt from the article -- to read the whole paper, you'll need to pay or use your university account -- click here if you wish to do so (view the whole paper):

American Journal of Clinical Nutrition, Vol. 86, No. 1, 261-262, July 2007
© 2007 American Society for Nutrition

LETTER TO THE EDITOR

Evidence-based medicine and vitamin E supplementation
Harri Hemilä
Department of Public Health, POB 41
University of Helsinki
Helsinki FIN-00014
Finland
E-mail: harri.hemila@helsinki.fi

Edgar R Miller, III

Johns Hopkins University School of Medicine
Baltimore, MD 21205

Dear Sir:

In a recent editorial in the Journal, Traber (1) recommended vitamin E supplementation for most adults in the United States. The logic behind her recommendation was as follows. First, Wright et al (2) reported in the same issue of the Journal that the lowest overall risk for mortality in the 19-y follow-up of the Alpha-Tocopherol Beta-Carotene (ATBC) Study occurred at serum vitamin E concentrations of 13–14 mg/L, and Traber labels that as an optimal concentration for reducing the risk of chronic disease. Second, 75% of men in the United States have serum vitamin E concentrations of <14.6 mg/L, which suggests widespread vitamin E deficiency in her opinion. Third, "given the dietary habits of most Americans," "optimal" concentrations of serum vitamin E are achievable only with vitamin E supplements (1).
...

In our opinion, the attitude toward vitamin E supplementation should be based on randomized controlled trials, which have not shown a benefit in preventing or treating chronic diseases, and not on observational studies, which are highly susceptible to biases that may remain even after statistical adjustment for confounders (5, 10). Although it is possible that some population groups may benefit from vitamin E supplementation, the evidence is so equivocal that it is inappropriate to make the sweeping recommendation for vitamin E supplementation in the United States that Traber makes. Implying health benefits of supplementation in the general population is contrary to the evidence; moreover, it puts people at risk if excess use occurs and will benefit only the industry that produces, promotes, and protects the continued sale of supplement products.

ACKNOWLEDGMENTS

Neither author had a personal or financial conflict of interest with respect to the study by Wright et al or the editorial by Traber.

1.  Traber M. How much vitamin E? Just enough! Am J Clin Nutr 2006;84:959–60 (editorial).
2.  Wright ME, Lawson KA, Weinstein SJ, et al. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr 2006;84:1200–7.
Free full text: http://www.ajcn.org/...resid=84/5/1200

...

5.  Omenn GS. Chemoprevention of lung cancer: the rise and demise of beta-carotene. Annu Rev Public Health 1998;19:73–99. http://www.ajcn.org/...3&link_type=MED

...

10. Lawlor DA, Davey Smith G, Bruckdorfer KR, Kundu D, Ebrahim S. Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? Lancet 2004;363:1724–7. http://www.ajcn.org/...7&link_type=MED

Of interest may be the following publication:

Conflict of interest policy for Editors of The American Journal of Clinical Nutrition (full text free).

Further thoughts or comments?

My comment? I don't know; if I were you, I'd ask your Doctor whether or not your diet and lifestyle implies you may need any particular supplement.

Take care.

woah, that's really serious.

Edited by Forever21, 19 October 2008 - 05:24 AM.

Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

Hello,
I wonder if someone who knows how to interpret these stats could explain what they mean exactly. What's RR and what does 1.16 for example mean? Is it high or low? And what's the other stuff?

Multivariate meta-regression analyses showed that low-bias risk trials (RR, 1.16; 95% CI, 1.05-1.29) and selenium (RR, 0.998; 95% CI, 0.997-0.9995) were significantly associated with mortality.