17/4/08

Patrick Holford

Anti-oxidants ARE important for good health

An extensive body of scientific research has shown that taking antioxidant supplements consistently over the long-term, can play a role in reducing the risk of chronic disease, therefore an updated meta-analysis published in the Cochrane Database of Systematic Reviews should not cause consumers to question the efficacy or safety of antioxidant supplements.

Patrick Holford one of the UK’s leading nutrition experts who provides the latest information on nutrition research on his website www.patrickholford.com, comments on the review, which claims potential harm from taking antioxidant supplements:

 “It’s a stitch up. If you look objectively at all the studies reviewed, which were chosen strictly for reducing mortality, and not for the many other benefits reported in other studies, Bjekalovic et al conclude ‘Beta-carotene, vitamin A and vitamin C, used singly or in combination with other antioxidants had no significant effect (on mortality)’, although a number of vitamin C studies did report reduced mortality. . .  and that ‘selenium used singly or in combination with other antioxidants significantly decreased mortality’”.

The only way this review could produce the negative results was by finding reasons to exclude most of the positive studies, including all the positive ones on selenium. Their basis for exclusion in a previous meta-analysis published in JAMA (Journal of the American Medical Association) has been heavily criticized in mainstream medical journals.

One of the world’s leading experts in this field, Dr Balz Frei, said “This is a flawed analysis of flawed data, and it does little to help us understand the real health effects of antioxidants, whether beneficial or otherwise.”

Moreover, although the authors claimed to be assessing antioxidant supplements for the prevention of mortality, they excluded all studies – 405 of them – that reported no deaths.

Patrick Holford says, “Anti-oxidants are not meant to be magic bullets and should not be expected to undo a lifetime of unhealthy habits. But when used properly, in combination with eating a healthy diet full of fruit and vegetables, getting plenty of exercise and not smoking, antioxidant supplements can play an important role in maintaining and promoting overall health.”

In practical terms this means that beta-carotene supplements, as we already knew, are best not taken singly by smokers. Vitamin E in high doses, should not be taken by those on cholesterol lowering medication. (These drugs stop you making CoQ10 turning vitamin E from an antioxidant into a potentially harmful oxidant.) Selenium and vitamin C are the most likely to be beneficial.

The Council for Responsible Nutrition

“Antioxidant Supplements for Prevention of Mortality in Healthy Participants and Patients with Various Diseases”

Bjelakovic G., et al., Cochrane Database of Systematic Reviews 2008, Issue 2

Background:

An updated meta-analysis examining the efficacy of antioxidant supplements in primary or secondary

prevention of mortality was published in The Cochrane Database of Systematic Reviews 2008, Issue 2, in April 2008.  The authors of the meta-analysis conclude that “there is no evidence to support antioxidant supplements for primary or secondary prevention of mortality and that vitamin A, beta-carotene, and vitamin E may in fact increase mortality. Future randomized trials could evaluate the potential effects of vitamin C and selenium for primary and secondary prevention. Such trials should be closely monitored for potential harmful effects. Antioxidant supplements need to be considered medicinal products and should undergo sufficient evaluation before marketing.”

These are the same authors that published similar meta-analyses in the Journal of the American Medical Association (JAMA) in February 2007 and in the Lancet in September 2004.  Although they have updated their meta-analysis, by handpicking additional studies and correcting a litany of minor mistakes made in previous versions, it is for all intents and purposes not a new study, nor is it truly new information.  In fact, it appears to be a systematic attempt by the authors to publish work that supports their own pre-determined conclusions about antioxidants and the way they should be regulated. 

The Council for Responsible Nutrition (CRN) believes this latest attempt to discredit antioxidants does nothing to change the practical implications for consumers, specifically a generally healthy population, that uses antioxidant supplements as part of their proactive wellness regimen in an attempt to fill nutrient gaps or help reduce the risk of chronic disease.   Healthy consumers can feel confident in continuing to take antioxidant supplements for the benefits they provide.  Consumers with serious illnesses, such as cancer, heart disease, liver disease, etc., should consult with their physician on anything they put into their body.  This updated meta-analysis does nothing to change those facts. 

There are a number of serious flaws with the meta-analysis, several of which were previously pointed out in response to the JAMA publication.  These flaws have not been addressed with this updated meta-analysis and include the following points:

• This meta-analysis only evaluated randomized, controlled trials (RCTs); there is an equally vast, if not more so, body of observational data involving antioxidants, which was not considered in this analysis.  Thus, this covers only a portion of the evidence base, so it cannot be considered comprehensive.

• The researchers identified 748 studies that could be included in this analysis; however, then determined that there were only 409 “eligible” RCTs. Of those, they excluded all but 67 studies. Thus, their conclusions are based on less than nine percent of the totality of available RCT evidence on antioxidant supplementation, and do not look at any research other than RCTs, which are in essence treatment trials.

• In selecting which RCTs to use, the researchers excluded any RCT in which no deaths were reported (405 articles), which begs the question of how one can properly evaluate whether a substance can prevent mortality when studies that demonstrate no harm are automatically excluded.

• The selected studies included studies examining different antioxidants (and in some cases, not even antioxidants), different doses, different populations with different health statuses, for different durations—in short, the authors combined heterogeneous studies and tried to make one generalized conclusion.  As the saying goes, it’s like comparing apples to oranges. 

• The authors relied on their own self-selected, and far from agreed upon, criteria for assessing bias (identical to that used in the last JAMA meta-analysis and criticized at that time by some highly respected researchers in the form of letters to the editor) where they established specific inclusion criteria. If any of the inclusion criteria from a scientific trial was deemed "inadequate", in the researchers’ opinions, then the study was deemed “high risk bias.” Not surprisingly, the studies that are considered “high risk bias” in this meta-analysis tend to be those that show a benefit to antioxidant supplementation, while those labeled as “low risk bias” tended to show harm.

• Only all-cause mortality was assessed in the review. As a result, the authors didn’t seek to eliminate deaths that may have been caused by accident, homicide, suicide, medical conditions that have nothing to do with supplementation or other circumstances. The authors intimated that all deaths were attributable to antioxidant supplements, ignoring other potential factors and did not offer any biological plausibility for their conclusions.

• These authors included vitamin A studies in their meta-analysis, despite the fact that experts within the scientific community universally agree that vitamin A does not function as an antioxidant and should not be characterized as one. The vitamin A RCTs that were included used extremely high doses of vitamin A, in some cases well above the established Tolerable Upper Limit (UL) established by the Dietary Reference Intakes (DRI), which may have significantly skewed the overall results of this analysis.

• Given the researchers’ own conclusion that antioxidant supplements should undergo pre-market approval, they betray their scientific duty and display their personal bias.  The researchers do not explore the regulatory practices anywhere in this 191-page paper and it is not clear that the researchers possess any expertise in the field of policy and public health. The entire paper, therefore, seems designed to support this regulatory agenda.

By Alan R. Gaby, MD

Healthnotes Newswire (April 17, 2008)—A new study published by the Cochrane Database of Systematic Reviews reports that taking antioxidant supplements does not prolong life, and that using certain specific antioxidants may slightly increase the risk of death. But vitamin users shouldn't take this report as seriously as its widespread publicity would suggest. The new study is essentially a rewritten version of a study published a year ago in the Journal of the American Medical Association that received heavy media coverage. The new study presents the same data that has already been reported and subsequently discredited.

Exclusion of certain trials skewed results

As before, the researchers looked at 67 clinical trials involving antioxidants and categorized them as either a high or low risk for error. The 20 clinical trials considered "high-bias risk" were excluded from the study—but just why the researchers felt the need to exclude these trials isn't clear and, unfortunately, excluding them significantly changed the results.

After excluding these trials, when the data from the remaining 47 trials (involving a total of 180,939 people) were pooled, taking any antioxidant increased the risk of death by 5%. For individual supplements, the risk was increased by 4% with vitamin E, 7% with synthetic beta-carotene, and 16% with vitamin A. All of these increases were statistically significant. Vitamin C and selenium had no significant effect on mortality.

Also as before, the reasons for the exclusion don't make scientific sense. Criteria the researchers used to decide whether a clinical trial should be considered reliable included the way in which participants were assigned to receive antioxidants or placebo, and whether the trial was double-blind. While these methods are usually the standard to which we agree most studies should be held, a study of this type doesn't require that kind of strict research design because a subtle imperfection in randomization method or a researcher's awareness of treatment assignments is unlikely to influence a result as objective as death. In other words, a researcher assigning a participant to a particular treatment or knowing which treatment someone is getting probably won't affect whether that person dies.

In the case of the current study, the so-called "high-bias risk" studies probably did not endanger the reliability of study results and there was, therefore, no compelling reason to exclude them. Had the researchers included those trials, there would have been no significant effect of antioxidant use in general, or of any specific antioxidant, on mortality.

Combining divergent studies not appropriate

Another weakness in this study was the pooling of the results of trials that had crucial differences, which led to inappropriate conclusions about the overall effects of antioxidants. Even though this study was published in a reputable and well-known medical journal, the Cochrane Database is not a publication that specializes in nutrition, and neither the authors nor the reviewers who read the material prior to publication appear to have been aware of how failing to adjust for the differences between these trials may have affected the study conclusions. (For specific examples of how these oversights might impact interpretation, see "Study details" at the end of this article.)

Previous research can't be ignored

Antioxidant supplements are used by tens of millions of people, with many uses supported by a wide body of research developed over many years and published in reputable medical journals that are dedicated more specifically to managing health through nutrition. Studies have shown, for example, that vitamin C may prevent or help treat heart disease, diabetes, high blood pressure, asthma, and more. Vitamin E is beneficial for intermittent claudication (difficulty walking caused by hardened arteries) and rheumatoid arthritis. Selenium may help prevent heart disease and certain types of cancer. Only rarely could a single study negate an entire body of research; rather, each new study adds to the medical "conversation" and helps determine the direction of future investigation.

Even within this study, despite its negative overall conclusions, some of the "low-bias risk" trials that were included showed a clear benefit from antioxidant supplementation. For example, in a study that lasted 7.5 years and included more than 13,000 people, modest doses of a combination of vitamin C, vitamin E, beta-carotene, selenium, and zinc reduced the death rate in men by 37%, although no effect was seen in women. Results like these should encourage further research to determine what doses and combinations of nutrients are safest and most effective for people of different ages and different genders and with different health concerns and lifestyles.

Even the most enthusiastic nutritional supplement supporters recognize the importance of a broad-spectrum approach to managing wellness and preventing disease that includes eating well, exercising, limiting exposure to toxins, and supplementing with nutrients that may not be obtained from the typical diet. Despite the concern that is likely to result from the republishing of this old research, it's important to put its findings into context and remember that there is well-demonstrated evidence that antioxidants may improve or prevent certain medical conditions and improve overall quality of life.

(Cochrane Database of Systematic Reviews 2008: CD007176. DOI:10.1002/14651858.CD007176.)

Study details:

As described in the above article, the pooling of the results of trials that had crucial differences, which led to inappropriate conclusions about the overall effects of antioxidants. For example:

• Beta-carotene—It is well established that synthetic beta-carotene increases the risk of lung cancer and death in smokers, possibly because of a toxic interaction with cigarette smoke. In nonsmokers, however, synthetic beta-carotene has no effect on mortality (natural beta-carotene, which has a different chemical structure, has not been well studied). Pooling all of the beta-carotene trials was therefore inappropriate, and led to the erroneous conclusion that synthetic beta-carotene supplements are bad for everyone, not just for smokers.

• Vitamin A—Researchers concluded that vitamin A increases risk of death by pooling five vitamin A trials, the largest of which studied smokers given a combination of vitamin A and synthetic beta-carotene. The increased mortality seen in the supplement group compared with the placebo group may have been due entirely to the beta-carotene and unrelated to the vitamin A.

In another of the vitamin A trials, patients with a previous skin cancer received 25,000 IU of vitamin A per day or a placebo for up to five years. During the entire trial, which included a follow-up period after vitamin A was discontinued, the death rate was slightly higher in the vitamin A group than in the placebo group (5.4% versus 4.6%). However, during the time that people were actually taking vitamin A, the death rate was slightly lower in the vitamin A group than in the placebo group (2.07% versus 2.11%). The bottom line: there is no way of knowing whether vitamin A was responsible for the small increase in mortality that occurred after supplementation was stopped.

In a third vitamin A trial, elderly nursing home residents were given a single dose of 200,000 IU of vitamin A or a placebo, and were then observed for signs of infection. During the follow-up period, the death rate was higher in the vitamin A group than in the placebo group (11.3% versus 7.1%); however, people receiving vitamin A were on average 4.8 years older than those receiving placebo. The higher death rate may have been entirely due to that age difference.

• Vitamin E—The issues surrounding vitamin E are complicated and some of the concern about adverse effects may be justified. In one large trial, the combination of vitamin E and beta-carotene was given to cigarette smokers. The increased mortality observed in that trial may have been entirely due to the beta-carotene and unrelated to vitamin E. In other trials, however, the adverse effect of vitamin E is difficult to dismiss.

It is important to note, however, that while vitamin E occurs in food in four different forms—alpha-, beta-, gamma-, and delta-tocopherol—virtually all of the research on vitamin E has used pure alpha-tocopherol. Alpha-tocopherol has a number of positive effects on cardiovascular function. But taking large amounts of it can deplete gamma-tocopherol, a component of the "vitamin E complex" that may be even more important for the heart than alpha-tocopherol is. Therefore, "mixed tocopherols," which contains all four naturally occurring forms of vitamin E, may be preferable to pure alpha-tocopherol, both in terms of safety and effectiveness.

• Selenium—It is curious that the study's authors paid such little attention to evidence of a beneficial effect. When all of the trials were pooled, selenium supplementation reduced mortality by 9%. When the "high-bias risk" trials were excluded, selenium's beneficial effect was even more pronounced (10% reduction) but, because of the smaller number of participants, that improvement was no longer statistically significant.

An expert in nutritional therapies, Chief Medical Editor Alan R. Gaby, MD, is a former professor at Bastyr University of Natural Health Sciences, where he served as the Endowed Professor of Nutrition. He is past-president of the American Holistic Medical Association and gave expert testimony to the White House Commission on Complementary and Alternative Medicine on the cost-effectiveness of nutritional supplements. Dr. Gaby has conducted nutritional seminars for physicians and has collected over 30,000 scientific papers related to the field of nutritional and natural medicine. In addition to editing and contributing to The Natural Pharmacy (Three Rivers Press, 1999), and the A–Z Guide to Drug-Herb-Vitamin Interactions (Three Rivers Press, 1999), Dr. Gaby has authored Preventing and Reversing Osteoporosis (Prima Lifestyles, 1995) and B6: The Natural Healer (Keats, 1987) and coauthored The Patient's Book of Natural Healing (Prima, 1999).

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