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ANTIOXIDANTS and DEATH from ALL CAUSES -

SUPPLEMENTARY ANALYSIS

A meta-analysis of 62 studies of antioxidants published in 2007 claimed little or no benefit for antioxidants in general, and claimed that Vitamin A, Beta Carotene and Vitamin E significantly increased mortality. ((Bjelakovic, G, JAMA 2007, 267:842)  The results of this study are inconsistent with the broader studies of antioxidant benefits developed in the Life Ahead analysis that I reference following..   A brief review of this study confirms the conclusions that use of very high Vitamin A and Beta Carotene amounts are not beneficial.  But this may be true only for the very high amounts of A and Beta used in these studies, and not for lower amounts useful for healthy people.  The conclusion on Vitamin E appears to be invalid. 

The tone of this report was that "Antioxidants  including Vitamin E have little or even negative confirmed value in reducing risk of death."  Other and more pertienet studies for healthy people that I cite show that antioxidants can have significant benefits in reducing risks of cardiovascular diseases, cancer, and all-cause death.   I find that a deficiency in antioxidants may be a major single health deficieny in many US diets, and a proper correction could prolong millions of lives.  The study data used in this meta analysis were impossible to view because results of each study were presented in three or more tables with no useful organization.  For this reason I have extracted the actual data of each useful included study in Table 1 following for convenient view  and re-analysis.

First, the conclusions were derived mostly from studies in which multiples of different nutrients were used. Any attempt using mathermatical methods to develop such values from such deeply intercorrelated factors is subject to considerable error.  Thus it is essential that such values developed from such mutiples be consistent with those developed directly from individual nutrients   I show following that this needed consistency was not obtained.

Second, the meta analysis included only results on clinical studies, many of which were very small and had little statistical value.  Antioxidants qppear to be related to atherosclerosis and are duration dependent, providing benefits of a reduced risk of about 3% per year of use. Clinical studies are most useful  for medicines and factors that provide near immediate benefits. But the expected results from usual durations of these studies can be much too small to be detected.  The large majority of about 100 observation studies of antioxidants  included in my present data base show each of the four antioxidants is significantly beneficial in reducing risk of cardiovascular diseases, cancer and all-cause death. These studies usually included a likely duration of use that could produce significant benefits.  An exception is that amounts of Vitamin A and Beta Carotene above about 5,000 IU and 6 mg respectively appear to be harmful to health.  Amounts of Vitamin E much above 400 IU also may not be beneficial.

A third problem with the meta analysis is that most clinical study data were secondary on populations that had suffered heart or another diseases.  Most such individuals would be taking a variety of medicines that could interact or or cancel benefits of antioxidants.  Only two  statistically useful primary studies of individual nutrients were found  included this meta analysis.

It is interesting to observe what the actual study data found about the individual antioxidants.

For Vitamin E. There were four primary studies of Vitamin E, as studies E-1 through E-4.  Each of these included only one or two death events in a comparison group. Such studes have no useful accuracy and can destroy usefulness of any statistical comparison that includes them. They are anecdotal and should not be included in any serious analysis of a factor.  I use a minimum of 10 events for recognizing a study for use in my Life Ahead program.  The meta analysis thus included no useful clinical study data on Vitamin E for presumably healthy people

There were 12 secondary studies of Vitamin E.   These are listed as studies E5 through E16 in Table 1.  The average duration was 2.1 years; average of 900 IU/day of Vitamin E, and average risk was a value 0f 0.942.  This happens to confirm the expected time related duration factor of a 3% per year benefit for Vitamin E. of 0.91

Five of these 12 secondary studes included too few events in a comparision group for scientific use.  If I subtract out the studies including only 1 or 2 events, an average result is a risk of  0.93.  If I subtract out all below 10 events the average is 0.95. The only important study is that of GISSI, E8.  Its results were a factor of 0.92, again close to my expected value of 0.90 for 3.5 years of nutrient duration.

Conclusion  This actual primary research on Vitamin E per se does not show a negative benefit, much less one that is "statistically significant and negative"   These results confirm a benefit that would  be expected from much other research on Vitamin E.  This is interesting  because most secondary clinical studies of antioxidant use for patients of diseases have not verified a useful effect for any antioxidant.

For Vitamin C:  There is just one study for Vitamin C, # C1 in the table following. It included just 3 events to produce a risk of 0.63 that his little significance.  Conclusion:  There is no information useful for Vitamin C included in this research that could support a claim of  either a benefit or negative.

For Selenium:  Just 3 studies were included.as S1 - S3. Both S2 and S3 have only one event in the comparison group and are worthless. The remaining study is the widely used and excellent one of Clark that showed a risk of 0.84 for  4.5 treatment years and 7.4 treatment plus followup years.  The expected value for Clark would be 0.87 for 4.5 years and 0.80 for 7.4 years,. again very close to my forecast for a 3% per year effect of duration..

Two studies included Vitamin E and Selenium:  CES-1 and CES-2. They both showed a benefit with the higher 0.87 risk value for CES-1 as the result most useful.  Two more studies included Vitamin E, Selenium, and 6 mg amounts of Beta Carotene that may be beneficial. .  Their average risk was 0.90, another  benefit. These four studies confirm further a likely benefit for Vitamin E and Selenium combinations from E5-E16 and SE- in amounts that would be expected from my Global Analysis of antioxidants.

For Vitamin A and Beta Carotene:  Three studies of Vitamin A included  2 useful ones, A2 and A3.  Both have extraordinary amount of Vitamin A, and or Beta Carotene far above the level of 5,000 IU of Vitamin A I found as maximum for health..  They showed as expected a negative benefit of 1.15.  The three studies of Beta Caroteine did average a 0.92 risk value, but other data have confirmed Beta Carotene in such high smounts to be harmful.   All of these values of course are subject to substantial statistical variability. Other studies not listed in Table 1 included multiple nutrients with large amounts of Vitamin A or Beta Carotene that could seriously confound the valuation of another included  nutrient . I do not feel that valid values of individual nutrients can be derived from results of multiple nutrients that include large amounts of Vitamin A or Beta Carotene by the method used in this study.

References:  For more extensive studies of antioxidants, please go to www.lifeahead.net, and access the 'Health Research Library'

Papers in the library include:

Vitamin A, Beta Carotene and Cardiovascular Disease

Vitamin A and Cancer

Vitamin C and Cardiovascular disease

Vitamin C and Cancer

Vitamin E and Cardiovascular Disease

Vitamin E and Cancer

Selenium and Heart Disease

Selenium and Cancer

Antioxidants and Death from all Causes

Antioxidants, All Causes, a Global Analysis

Antioxidants, Death from All Causes, a Supplementary Analysis

                                                                                                       Table 1

                                                  Antioxidant Supplements and Risk of Death from All Causes